Glutarimide derivatives, use thereof, pharmaceutical composition based thereon and methods for producing glutarimide derivatives

ABSTRACT

The present invention relates to novel biologically active glutarimide derivatives of general formula I or pharmaceutically acceptable salts thereof, their use as an agent for the treatment of upper respiratory tract diseases, pharmaceutical compositions comprising the glutarimide derivatives of general formula I, methods for preparing the glutarimide derivatives of general formula I by heating a dicarboxylic acid monoamide of general formula II with a dehydrating agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Stage application under 35 U.S.C.§371 of International Application PCT/RU2014/000264 (published as WO2014/168522 A1), filed Apr. 10, 2014, which claims priority toApplication RU 2013116826, filed Apr. 12, 2013. Benefit of the filingdate of each of these prior applications is hereby claimed. Each ofthese prior applications is hereby incorporated by reference in itsentirety.

The invention relates to novel biologically active compounds, inparticular to glutarimide derivatives or pharmaceutically acceptablesalt thereof, to use thereof as agents for the prevention and treatmentof upper respiratory tract diseases, and to methods for preparing saidcompounds.

BACKGROUND

Upper respiratory tract chronic diseases are the most common diseases inchildren and adults throughout the world. The upper respiratory tractchronic diseases include, in particular, rhinosinusitis.

Rhinosinusitis is an inflammation of the mucous tunic of the nose andparanasal sinuses (PNS) and is the most actual problem in theotorhinoryngology (Fokkens W. J., Lund V. J., Mullol J. et al., EuropeanPosition Paper on Rhinosinusitis and Nasal Polyps. Rhinology 2007; 45;20:1-139). A cause of rhinosinusitis almost always is mucous congestion,blockage of natural ostia of the PNS, and a disturbance in theirventilation when the mechanism of mucociliary clearance suffers sincesaid mechanism is an important primary innate mechanism protecting therespiratory tract from damaging action of inhaled pollutions, allergensand causal organisms.

Acute rhinosinusitis is a frequent complication of an acute respiratoryviral infection (ARVI).

Today, the rhinosinusitis therapy starts with administration ofcorticosteroids since they have a pronounced anti-inflammatory effect.Corticosteroids are used as monotherapy or in combination withantibiotics. More severe forms of rhinosinusitis require the use ofantibiotics. Main corticosteroids are fluticasone, budesonide andmometasone. In the treatment of rhinosinusitis, corticosteroids areprescribed for long-term use, which may cause side effects andtolerance. Side effects are, as a rule, the manifestation of theintrinsic glucocorticosteroid action of these medicaments but in adegree that exceeds the physiological norm.

The prescribed antibiotics are, in general, penicillin antibiotics(amoxicillin, penicillin V) or non-penicillin antibiotics (macrolides,tetracycline) (Fokkens W. J., Lund V. J., Mullol J. et al., EuropeanPosition Paper on Rhinosinusitis and Nasal Polyps. Rhinology 2007; 45;20:1-139).

Thus, there is a need for novel preparations that would intensify thetreatment of rhinosinusitis and weaken an inflammatory reaction whilereducing suppurative inflammation and subsurface injuries in the form ofnecrotic defects, and would prevent the disease from becoming chronic.Thus, the objective of the present invention is to develop and introduceinto practice novel medicaments for the treatment of rhinosinusitis.

Viral infections are a serious health problem. There are no developedantiviral drugs against most hazardous and dangerous viral infections,and the existing medicaments are often toxic to humans or insufficientlyeffective. Most of existing or under-development drugs act through aspecific interaction with specific viral proteins. Such drugs have alimited spectrum of action and promote a rapid emergence of resistantviral variants. Classes IV and V of the Baltimore virus classificationsystem include viruses containing single-stranded (+) or (−) RNA. ClassIV includes representatives of the Enterovirus genus of thePicornaviridae family and the Coronaviridae family, and class V includesa respiratory syncytial virus (RSV) of the Paramyxoviridae family andinfluenza virus of the Orthomyxoviridae family.

The recited groups of viruses have developed an effective strategy ofinhibiting the cellular antiviral program. Such aggressive strategy ofinhibiting the system of the cellular antiviral protection leads to ahigh contagiousness and a high pathogenicity of these groups of viruses,which fact is confirmed by the list of diseases caused by the virusesbelonging to the Enterovirus genus (poliomyelitis, viral rhinitis(rhinoviral cold)). Today, among viruses of the Enterovirus genus, humanrhinoviruses cause the biggest problem. Rhinoviruses, which arereplicated in the nasopharyngeal mucosal cells, are a causative agent ofupper respiratory tract diseases in humans. Rhinoviruses are causativeagents of at least 80% of cold-related diseases. Apart from the enormouseconomic damage (20 million humans/hour annually in the U.S.),rhinovirus infections cause a large number of complications such assinusitis and otitis media and are frequently detected in virologicalexamination of children with pneumonia. In asthmatic children,rhinovirus infection is also a cause of acerbations in 80% cases. Inadults, rhinovirus may cause exacerbations of both asthma and chronicobstructive pulmonary disease, chronic bronchitis, and mucoviscidosis.Rhinovirus was isolated in pneumonia patients with immunodeficiencyconditions.

Since there are more than 100 antigenic types of rhinovirus, this makesit impossible to develop an effective vaccine (Palmenberg, A. C; Spiro,D; Kuzmickas, R; Wang, S; Djikeng, A; Rathe, J A; Fraser-Liggett, C M;Liggett, S B (2009). “Sequencing and Analyses of All Known Humanrhinovirus Genomes Reveals Structure and Evolution”. Science 324 (5923):55-9. doi:10.1126/science. 1165557. PM1D 19213880). In addition, thereis no an effective chemotherapeutic agent for the treatment ofrhinovirus infection.

Coxsackie virus infection (HCXV) is a large group of diseasescharacterized by pronounced clinical polymorphism. Coxsackie virusinfection can manifest itself in meningitis, paralysis, acuterespiratory disorders, pneumonia, haemorrhagic conjunctivitis,myocarditis, hepatitis, diabetes and other syndromes. According to themodern classification of viruses, human enteroviruses belonging to theEnterovirus genus are divided into 5 species: 1) poliovirus; 2) humanenteroviruses A; 3) human enteroviruses B; 4) human enteroviruses C; and5) human enteroviruses D. Various serotypes of Coxsackie virus belong tothe following enterovirus species: Human enterovirus A (Coxsackieviruses A2-8, 10, 12, 14, and 16); Human enterovirus B (Coxsackieviruses A9, B1-6); Human enterovirus C (Coxsackie viruses A1, 11, 13,15, 17-22, and 24).

Coxsackie viruses, like other human enteroviruses, are ubiquitousthroughout the world. In the temperate countries, their maximumcirculation is observed in the summer-autumn season. The viruses arecharacterized by a high invasiveness, thus promoting their rapid spreadin the human population. Coxsackie viruses are often the cause of“sudden” outbreaks in organized children's groups and hospitals;interfamilial spread of the infection occurs as well. A high variabilityof the viral genome plays an important role in the epidemiology ofCoxsackie virus and other enterovirus infections. As a consequence,various serotypes are able to cause different pathology in certaincircumstances. On the other hand, the same clinical syndrome may becaused by different serotypes and different enterovirus species. Geneticvariability, selection and rapid spread of modified viruses result inlarge-scale outbreaks of the diseases, the etiology of which has norelation to these viruses, or their circulation was not recorded for along time.

The primary replication of Coxsackie virus occurs in the nasopharynx-and gut-associated lymphoid tissue. It causes local lesions expressed inthe symptoms of ARD, herpangina, pharyngitis, etc. In the throat thevirus is detected until the seventh day, and is excreted with faeces for3-4 weeks (in case of immunodeficiency for several years). Viremia, as aresult of which the virus penetrates the target organs, follows theprimary replication of the virus. For Coxsackie viruses such targetorgans may be the brain and spinal cord, meninges, upper respiratorytract, lungs, heart, liver, skin, etc. Coxsackie virus B can causesevere generalized pathological processes in newborns, resulting innecrosis in the heart, brain and spinal cord, liver and kidneys. Theviruses cause the following clinic syndromes: aseptic meningitis(Coxsackie viruses A2, 3, 4, 6, 7, 9, 10, and B1-6); acute systemicdisease in children with myocarditis and meningoencephalitis (Coxsackieviruses D1-5); paralysis (Coxsackie viruses Al, 2, 5, 7, 8, 9, 21, andB2-5); herpangina (Coxsackie viruses A2, 3, 4, 5, 6, 8, and 10); acutepharyngitis (Coxsackie viruses A10, 21); contagious rhinitis (Coxsackieviruses A21, 24); damage of the upper respiratory tract (Coxsackieviruses A9, 16, and B2-5) (16); pericarditis, myocarditis (Coxsackieviruses B1-5); hepatitis (Coxsackie viruses A4, 9, 20, and B5); diarrheaof newborns and infants (Coxsackie viruses A18, 20, 21, 24); acutehaemorrhagic conjunctivitis (Coxsackie viruses A24); Hand, Foot andMouth Disease (Coxsackie viruses A5, 10, 16); exanthemata (Coxsackieviruses A4, 5, 6, 9, 16); pleurodynia (Coxsackie viruses B3, 5); rash(Coxsackie viruses B5); fever (Coxsackie viruses B1-6); There are absentspecific chemotherapeutic agents for the treatment of Coxsackie virusinfections. Pathogenic and symptomatic therapy is applied, depending onthe clinical form of the disease.

The Paramyxoviridae family includes the representatives of the genusRespirovirus (human parainfluenza virus types 1, 2, 3, 4, and 5) andgenus Pneumovirus (respiratory-syncytial virus).

Paramyxoviruses are an important class of viruses that are associatedwith respiratory diseases. Respiratory-syncytial virus (RSV) is known tobe a dominant pathogen of the lower respiratory tract throughout theworld.

RSV is a pathogen in newborns and infants and is a causative agent of atleast 70% of severe viral bronchitis and/or pneumonias, the majoritypart of which is characterized by wheezing and dyspnea. Thesebronchiolites are the most common cause of hospitalization in the winterseason during the first year of child's life. RSV also causesbronchiolitis, pneumonia and chronic obstructive respiratory disease inhumans of all-ages and makes a significant contribution to an excessmortality in the winter season.

In infants and young children, RSV is the main inducer of rales andexacerbations of asthma. RSV-infected adults are reported to have anincreased risk of exacerbations of asthma leading to hospitalization,relative to health patients (Falsey A R, Hennessey P A, Formica M A, CoxC, Walsh E E. Respiratory syncytial virus infection in elderly andhigh-risk adults. N Engl J Med. 2005; 352(17):1749-1759).

RSV takes a leading position on the number of fatal cases among viralinfections. Only the U.S. spends $2.4 billion on the treatment of virallower respiratory tract diseases in children. By one year of age, 50-65%of children have been infected with this virus, and by two years of age,almost 100% of children have been infected. In addition to prematurenewborns and older persons, a high-risk group includes persons withdiseases of the cardiovascular, respiratory and immune systems. Based onpublished and non-published data, it has been calculated that RSV causesin the world 33.8 millions of cases of episodic acute lower respiratorytract infections (LRTI), 3.4 millions of severe LRTI cases requiringhospitalization, and 66,000-99,000 of fatal cases among children underthe age of 5 (Nair H, Nokes D J, Gessner B D, Dherani M, Madhi S A,Singleton R J, O'Brien K L, Roca A, Wright P F, Bruce N, Chandran A,Theodoratou E, Sutanto A, Sedyaningsih E R, Ngama M, Munywoki P K,Kartasasmita C, Simoes E A, Rudan I, Weber M W, Campbell H. Globalburden of acute lower respiratory infections due to respiratorysyncytial virus in young children: a systematic review andmeta-analysis. Lancet; 375: 1545-55). Only in the U.S., 90,000 prematurenewborns, 125,000 hospitalized newborns, more than 3.5 million childrenunder the age of 2, and 175,000 hospitalized adults need the treatmentevery year (Storey S. Respiratory syncytial virus market. Nat Rev DrugDiscov 2010; 9: 15-6.). In 1 year of age, about a third of childrenhospitalized with acute bronchiolitis have an episodic dyspnea and anincreased sensitivity to common allergens (Schauer U, Hoffjan S,Bittscheidt J, Kochling A, Hemmis S, Bongartz S, Stephan V. RSVbronchiolitis and risk of wheeze and allergic sensitisation in the firstyear of life. Eur Respir J 2002; 20: 1277-83). These symptoms may returnin following years (Sigurs N, Gustafsson P M, Bjarnason R, Lundberg F,Schmidt S, Sigurbergsson F, Kjellman B. Severe respiratory syncytialvirus bronchiolitis in infancy and asthma and allergy at age 13. Am JRespir Crit Care Med 2005; 171: 137-41). Bronchiolitis may also becaused by rhinovirus, coronovirus, influenza and parainfluenza viruses,and adenovirus. However, among the all recited viruses, RSV is the mostfrequent cause of hospitalization due to bronchiolitis. An adaptiveimmunity formed as a result of a past RSV infection both in children(with an immature immune system) and in adults are short-term and doesnot provide a complete antiviral protection. This fact leads toreinfections occurred throughout life. In first months of life, theblood of newborns comprises maternal anti-RSV antibodies; however, theydo not protect a child.

It should be noted that the only chemotherapeutic agent exerting somebeneficial effects in infections caused by (+) and (−) RNA viruses isribavirin. However, ribavirin is a relatively toxic drug frequentlycausing anemia. Its main feature is a long-term storage in red bloodcells. As a result, traces of ribavirin are detected even 6 months afterthe end of therapy. Also, there are reports about teratogenicity ofribavirin.

Influenza virus belongs to the Orthomyxoviridae family comprising fourgenera: influenza viruses A, B, and C and thogotoviruses (sometimesreferred to as influenza D virus). Humans can be infected by influenzaviruses A, B and C, but only type A causes pandemics posing a seriousthreat for humans. According to the WHO data, influenza causes 3-5million cases of severe diseases and 250,000 to 500,000 fatal casesevery year throughout the world.

Influenza virus is also exhaled by patients with exacerbations ofasthma; however, the number of cases is 1-9% of other viruses.

Two main surface glycoproteins of influenza virus, hemagglutinin andneuraminidase, are responsible for the virus attachment and the releasethereof from a host cell and, at the same time, are the main target forantibodies. Type A viruses are subdivided into subtypes on the basis ofdifferent combinations of 16 variants of hemagglutinin and 9 variants ofneuraminidase. All known subtypes have been confirmed for wild birdswhich are considered to be a natural host for influenza type A viruses.Only three subtypes, in particular A (H1N1), A (H2N2) and A (H3N2), areknown in the human population. These viruses together with influenzatype B viruses are responsible for annual epidemics of variousseverities. The diversity of influenza viruses is a geneticallydetermined feature. The segmented negative-sense RNA genome organizationof influenza virus facilitates the exchange of genomic segments(so-called re-assortment) between different strains during mixedinfection. In addition, the lack of proofreading activity in thepolymerase of influenza virus leads to a high mutation rate in the virusgenes, thus leading to regular appearance of influenza strains with“new” antigenic properties. If the change is sufficient to overcome thepre-existing immunity in the human population, the virus is capable ofcausing an epidemic. When the human population is completely naive to anewly emerging variant, the virus can readily cause infection and betransmitted from infected to uninfected persons, and cause a pandemic.The above-indicated peculiarities determine difficulties in the creationof anti-influenza vaccines. There are known two classes of themedicaments inhibiting the M2 protein or neuraminidase of influenzavirus. Adamantane derivatives (amantadine and rimantadine) are activeagainst influenza type A viruses (but not against type B). Theneurominidase-inhibiting medicaments are zanamivir and oseltamivir. Bothmedicaments are preferably effective at the early stage.

The most common method for synthesis of dicarboxylic acid imides is amethod of thermal cyclization comprising heating a dicarboxylic acid ora derivative thereof, such as anhydride, diester and the like, with aprimary amine or an amide thereof. The yield of cyclic imides is usually80%; however, since the process is conducted under a high temperature,it may be used only for the synthesis of thermally stable imides[Weigand-Hilgetag, Experimental Methods in Organic Chemistry [Russiantranslation], (N. N. Suvorov, ed.), Moscow, Khimiya, 1968; p. 446].

The article of Yong Sup Lee et al., Studies on the site-selectiveN-acyliminium ion cyclazation: synthesis of (±)-glochidine and(±)-glochidicine. Heterocycles. Vol 37. No 1. 1994, discloses thepreparation of succinimide histamine by fusing histamine dihydrochlorideand succinic anhydride under heating of the initial reactants to200-230° C. for 40 minutes.

The international publication of patent application WO2007/000246discloses a method for synthesis of glutarimides by alkylation ofpiperidine-2,6-dione and pyrrolidin-2,5-dione with corresponding haloderivatives in DMF, followed by separation of the target substitutedimides by preparative chromatography, which is not applicable for thesynthesis of macro amounts.

The article of Shimotori et al, Asymmetric synthesis of 5-lactones withlipase catalyst. Flavour and Fragrance Journal.-2007.-V. 22.-No. 6.-pp.531-539, describes a method for preparing cyclic imides by cyclizationof monoamides of corresponding dicarboxylic acids by using a dehydratingagent as a carboxylic group-activating reactant, such as aceticanhydride.

The article of Ito et al; Chemoselective Hydrogenation of ImidesCatalyzed by CpRu(PN) Complexes and Its Application to the AsymmetricSynthesis of Paroxetine. // Journal of the American ChemicalSociety.-2007.-V. 129.-No. 2.-pp. 290-291, describes a method forpreparing cyclic imides by cyclization of monoamides of correspondingdicarboxylic acids by using a dehydrating agent as a carboxylicgroup-activating reactant, such as acetyl chloride.

The article of Polniaszek, et al; Stereoselective nucleophilic additionsto the carbon-nitrogen double bond. 3. Chiral acyliminium ions. //Journal of Organic Chemistry.-1990.-V. 55.-No. 1.-pp. 215-223, teaches amethod for preparing cyclic imides by cyclization of monoamides ofcorresponding dicarboxylic acids by using a dehydrating agent as acarboxylic group-activating reactant, such as carbonyldiimidazole.

The article of Ainhoa Ardeo et al, A practical approach to the fusedP-carboline system. Asymmetric synthesis of indolo[2,3-α]indolizidinonesvia a diastereoselective intramolecular α-amidoalkylation reaction./Tetrahedron Letters. 2003. 44. 8445-8448, discloses a method forpreparing cyclic imides from a primary amine and a correspondinganhydride, wherein a dehydrating agent is an excess of glutaric orsuccinic anhydride. In particular, said article provides a scheme of thesynthesis of glutarimidotryptamine and succinimidotryptamine fromtryptamine and anhydride of a corresponding acid under boiling in aceticacid. The yield of glutarimidotryptamine and succinimidotryptamineprepared by said method is 67% and 81%, respectively.

The publication of international application WO 2007/007054 disclosessuccinimide and glutarimide derivatives of general formula (I) havinginhibitory action on DNA methylation in cells, in particular tumorcells. Compounds disclosed in said article are prepared by an additionreaction between an amino derivative comprising a hydrocarbon chain anda corresponding anhydride or acid, or ether, followed by optionalcyclization optionally in the presence of a base.

Thus, the objective of the present invention is to provide novelnon-toxic glutarimide derivatives which are effective in the treatmentof upper respiratory tract diseases.

SUMMARY OF THE INVENTION

The present invention relates to glutarimide derivatives of generalformula I:

wherein m is an integer from 0 to 2;

R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁, eachindependently represents hydrogen, C₁-C₆alkyl; —NH₂, —NHC₁-C₆alkyl,hydroxyl, or C₁-C₆alkoxy;

R₂ is hydrogen, C₁-C₆alkyl, —C(O)OH, —C(O)OC₁-C₆alkyl;

R₃ is:

1) a 5-membered saturated or unsaturated heterocyclic group comprisingfrom 1 to 4 heteroatoms selected from N, O and S, optionally substitutedwith 1 to 3 substituents selected from halogen, C₁-C₆alkyl, C₁-C₆alkoxy,—C(O)OH, —C(O)OC₁-C₆alkyl, —NHC(O)C₁-C₆alkyl, phenyl, or pyridinyl;

2) a 6-membered saturated or unsaturated heterocyclic group comprisingfrom 1 to 2 heteroatoms selected from N and O, optionally substitutedwith a group selected from halogen and C₁-C₆alkyl;

3) a 5-membered unsaturated heterocyclic group comprising from 1 to 3heteroatoms selected from N and S, optionally substituted with 1 or 2substituents selected from C₁-C₆alkyl, condensed with a 6-memberedunsaturated nitrogen-containing cyclic or heterocyclic group optionallysubstituted with 1 or 2 substituents selected from hydroxyl, halogen orC₁-C₆alkyl;

4) a 6-membered unsaturated cyclic or heterocyclic group comprising from1 to 2 nitrogen atoms, condensed with a 5- or 6-membered unsaturatedheterocyclic group comprising from 1 to 3 heteroatoms selected from Nand S; or

5) a group of the formula:

or a pharmaceutically acceptable salt thereof,

with a proviso that the compound is not a compound, wherein:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is —C(O)OCH₃, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 1, R^(a) ₁ is an amino group and R^(b) ₁, R^(c) ₁, R^(d) ₁,R^(e) ₁, and R^(f) ₁ are hydrogen, or R^(e) ₁ is an amino group andR^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, and R^(f) ₁ are hydrogen and R₂ ishydrogen, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is —C(O)OH, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is —C(O)OH, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 2, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 2, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

The present invention also relates to a medicament for the treatment ofupper respiratory tract diseases, wherein the medicament is aglutarimide derivative of general formula (I) or a pharmaceuticallyacceptable salt thereof.

Another object of the present invention is a pharmaceutical compositionfor the treatment of upper respiratory tract diseases, comprising aneffective amount of a glutarimide derivative of general formula (I) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

The present invention further relates to a method for treating upperrespiratory tract diseases, comprising administering to a patient aneffective amount of a glutarimide derivative of general formula (I) or apharmaceutically acceptable salt thereof.

The present invention also relates to a method for preparing aglutarimide derivative of general formula (I) or a pharmaceuticallyacceptable salt thereof by heating a dicarboxylic acid monoamide ofgeneral formula (II)

wherein m is an integer from 0 to 2;

R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁, eachindependently represents hydrogen, C₁-C₆alkyl; —NH₂, —NHC₁-C₆alkyl,hydroxyl, or C₁-C₆alkoxy;

R₂ is hydrogen, C₁-C₆alkyl, —C(O)OH, or —C(O) C₁-C₆alkyl;

R3 is:

1) a 5-membered saturated or unsaturated heterocyclic group comprisingfrom 1 to 4 heteroatoms selected from N, O and S, optionally substitutedwith 1 to 3 substituents selected from halogen, C₁-C₆alkyl, C₁-C₆alkoxy,—C(O)OH, —C(O)OC₁-C₆alkyl, —NHC(O)C₁-C₆alkyl, phenyl, or pyridinyl;

2) a 6-membered saturated or unsaturated heterocyclic group comprisingfrom 1 to 2 heteroatoms selected from N and O, optionally substitutedwith a group selected from halogen and C₁-C₆alkyl;

3) a 5-membered unsaturated heterocyclic group comprising from 1 to 3heteroatoms selected from N and S, optionally substituted with 1 or 2substituents selected from C₁-C₆alkyl, condensed with a 6-memberedunsaturated nitrogen-containing cyclic or heterocyclic group optionallysubstituted with 1 or 2 substituents selected from hydroxyl, halogen orC₁-C₆alkyl;

4) a 6-membered unsaturated cyclic or heterocyclic group comprising from1 to 2 nitrogen atoms, condensed with a 5- or 6-membered unsaturatedheterocyclic group comprising from 1 to 3 heteroatoms selected from Nand S; or

5) a group of the formula:

with a dehydrating agent in an organic solvent.

DETAILED DESCRIPTION OF THE INVENTION

Preferred compounds according to the invention are compounds of generalformula I, wherein

m is an integer from 0 to 2;

R^(a) ₁ and R^(b) ₁ are hydrogen, methyl, amino, or hydroxyl;

R^(c) ₁ and R^(d) ₁ are hydrogen, methyl, amino, or hydroxyl;

R^(e) ₁ and R^(f) ₁ are hydrogen or methyl;

R₂ is hydrogen, methyl, carboxyl, methoxycarbonyl, or ethoxycarbonyl;

R₃ is

a group selected from:

The most preferred compounds according to the present invention arecompounds represented in Table 1.

TABLE 1 Number of a compound Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

The pharmaceutically acceptable salts of the compounds according to thepresent invention can be selected from additive salts of organic acids(for example, formiate, acetate, maleate, tartrate, methanesulfonate,benzenesulfonate, toluenesulfonate, etc.), additive salts of inorganicacids (for example, hydrochloride, hydrobromide, sulphate, phosphate,etc.), and salts with amino acids (for example, an aspartic acid salt, aglutamic acid salt, etc.), preferably chlorohydrates and acetates.

The most preferred known compounds that can be used in thepharmaceutical composition and methods for the treatment according tothe present invention are glutarimide derivatives represented in Table2.

TABLE 2 The number of a compound Structure 116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

Compounds according to the present invention can be prepared by a methodcomprising heating of initial dicarboxylic acid monoamides of generalformula II with a dehydrating agent in an organic solvent or in thedehydrating agent, optionally with sodium acetate.

Compounds of general formula II and methods for preparing thereof aredisclosed in the publication of international application WO1999/001103.

The step of heating is preferably performed at temperature of 90 to 120°C., more preferably at 100° C., and more preferably under boiling.

The dehydrating agent used in the method may be selected fromdixarboxylic acid anhydrides, organic acid chloroanhydrides, andcarbonyldiimidazole.

A preferred dehydrating agent used in the method is glutaric anhydride,propionic anhydride, acetic anhydride, acetic acid chloroanhydride, orcarbonyldiimidazole. The most preferred variant is propionic anhydridein toluene, glutaric anhydride preferably in dimethylformamide, aceticanhydride in dioxane, or acetic acid chloroanhydride in acetic acid.

The most preferred variant of the method is a method, wherein adehydrating agent and a solvent are acetic acid and heating is performedat 90-100° C.

If a compound comprises additional functional groups (for example, OH,NH₂, COOH), they must be previously protected with conventionalprotective groups commonly used in the organic synthesis, such asbenzyloxycarbonyl, benzyl, and acetyl groups. Upon completion of thesynthesis, these groups are optionally removed, for example, byhydrogenation.

The claimed methods for preparing N-substituted glutarimides of generalformula I substituted on the nitrogen atom are simple in implementation,conducted under quite mild conditions, are free of by-products, readilyreproducible, and provide target products with a high yield (up to 82%)and of a high purity.

Glutarimide derivatives of general formula I are therapeutically activeagainst upper respiratory tract diseases.

In particular, compounds according to the present invention are usefulin the treatment of the upper respiratory tract diseases of bacterial,viral, or viral and bacterial etiology, or caused by other factors. Inparticular, such diseases are rhinosinusitis, diseases caused byRNA-comprising viruses, such as rhinovirus, Coxsackie virus, respiratorysyncytial virus and influenza virus, for example, exacerbations ofasthma, chronic obstructive pulmonary disease, bronchitis andmucoviscidosis, which are caused by rhinovirus, influenza virus and/orrespiratory syncytial virus.

The compounds according to the present invention are administered in aneffective amount that provides a desired therapeutic effect.

The compounds of general formula (I) may be administered orally,topically, parenterally, intranasally, by inhalation, and rectally in aunit dosage form comprising non-toxic pharmaceutically acceptablecarriers. The term “oral administration” as used in the presentinvention means subcutaneous, intravenous, intramuscular or intrathoricinjection or infusion.

The compounds according to the present invention can be administered toa patient at a dose of from 0.1 to 100 mg/kg of the body weight oncedaily, preferably at a dose of from 0.25 to 25 mg/kg one or more times aday.

In addition, it should be noted that a particular dose for a particularpatient depends on many factors, including the activity of a certaincompound, patient's age, body weight, gender, general health conditionand diet, the time and route of administration of a pharmaceutical agentand the rate of its excretion from the body, a specific combination ofdrugs, and the severity of a disease in an individual to be treated.

The pharmaceutical compositions according to the present inventioncomprise a compound of general formula (I) in an amount effective toachieve a desired technical result, and can be administered in a unitedosage form (for example, in a solid, semi-solid, or liquid form)comprising the compounds according to the present invention as an activeagent in a mixture with a carrier or an excipient suitable forintramuscular, intravenous, oral and sublingual administration,administration by inhalation, intranasal and intrarectal administration.The active ingredient can be in a composition together with conventionalnontoxic pharmaceutically acceptable carriers suitable for themanufacture of solutions, tablets, pills, capsules, coated pills,emulsions, suspensions, ointments, gels, and any other dosage forms.

As an excipient, various compounds can be used, such as saccharides, forexample, glucose, lactose, of sucrose; mannitol or sorbitol; cellulosederivatives; and/or calcium phosphates, for example, tricalciumphosphate or calcium hydrophosphate. As a binder, the followingcompounds can be used, such as a starch paste (for example, corn, wheat,rice, or potato starch), gelatin, tragacanth, methylcellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone. Optionally used disintegrants are theabove-mentioned starches and carboxymethylstarch, crosslinkedpolyvinylpyrrolidone, agar-agar, or alginic acid or a salt thereof, suchas sodium alginate.

Additives that can be optionally used are flowability-control agents andlubricants, such as silicon dioxide, talc, stearic acid and saltsthereof, such as magnesium stearate or calcium stearate, and/orpropylene glycol.

The core of a coted pill is usually coated with a layer that isresistant to the action of gastric acid. For this purpose a concentratedsolution of saccharides can be used, wherein said solutions canoptionally comprise gum arabic, talc, polyvinylpyrrolidone, polyethyleneglycol, and/or titanium dioxide, and suitable organic solvents or amixture thereof.

Stabilizers, thickening agents, colorants, and fragrances also can beused as additives.

As an ointment base, there are usable hydrocarbon ointment bases, suchas white Vaseline and yellow Vaseline (Vaselinum album and Vaselinumflavum, respectively), Vaseline oil (Oleum Vaselini), and white ointmentand liquid ointment (Unguentum album and Unguentum flavum,respectively), wherein solid paraffin or wax can be used as an additiveproviding a firmer texture; absorptive ointment bases, such ashydrophilic Vaseline (Vaselinum hydrophylicum), lanoline (Lanolinum),and cold cream (Unguentum leniens); water-removable ointment bases, suchas hydrophilic ointment (Unguentum hydrophylum); water-soluble ointmentbases, such as polyethylene glycol ointment (Unguentum GlycolisPolyaethyleni); bentonite bases; and others.

A base for gels may be selected from methylcellulose, sodiumcaboxymethylcellulose, oxypropylcellulose, polyethylene glycol orpolyethylene oxide, and carbopol.

In preparing a unit dosage form, the amount of an active agent used incombination with a carrier can vary depending on a recipient to betreated and on a particular route of administration of a therapeuticagent.

For example, when the compounds according to the present invention areused in the form of a solution for injection, the amount of the activeagent in this solution is up to 5 wt. %. A diluent may be selected froma 0.9% sodium chloride solution, distilled water, a Novocain solutionfor injection, Ringer's solution, a glucose solution, and specificsolubilizing adjuvants. When the compounds according to the presentinvention are administered in tablet or suppository form, their amountis up to 200 mg per unit dosage form.

Dosage forms according to the present invention are prepared byconventional procedures, such as blending, granulation, forming coatingpills, dissolution, and lyophilization.

It should be noted that the compounds according to the present inventionare biologically active in doses by two-three orders of magnitude lowerthan the doses of comparative known medicaments and have almost the sameefficiency. In addition, there are no registered adverse effects causedby these compounds and they do not have contraindications foradministration as well. Furthermore, the toxicity tests of the compoundsaccording to the present invention showed no registered fatal casesamong experimental animals at an oral dose of 3000 mg/kg.

The detailed description of the compounds according to the presentinvention, their preparation and studies of their activity are disclosedin the following examples that are intended for purposes of illustrationonly and are not intended to limit the scope of the invention.

EXAMPLES OF SYNTHESIS OF GLUTARIMIDE DERIVATIVES OF GENERAL FORMULA I

Materials and Methods

Identity of obtained compounds were assessed by the thin-layerchromatography (TLC) method on plates “Kieselgel 60 F254” (“Merck”,German) in a solvent system: chloroform-methanol (8:2) (1); andchloroform-methanol (9:1) (2).

Chromatograms and electrophoregrams were stained withchloro-tetramethylbenzene reagent and Pauly's reagent.

Fourier-IR spectra were recorded on a “Magna 750” spectrometer with KBrtablets (“Nicolet” (US)).

Shimadzu Analytical HPLC SCL10Avp LC/MS system was used for the analysisof multicomponent mixtures on a mass spectrometer PE SCIEX API 165 (150)(Canada).

Analytical-scale reversed phase HPLC was performed on a Shimadzu HPLCchromatograph under the following conditions: column: Symmetry C18,250×4.6 mm; elution gradient system: water with 0.1% HCOOH:acetonitrilewith 0.1% HCOOH (condition A); column: Merk.LiChroCART 250×4 mm 5 μm.LiChrospher 100RP-8E 5 μm. C8, Serial number 1.50837.0001; elutiongradient system: an ammonium acetate buffer solution (pH7.5):acetonitrile (condition B); a buffer with 0.0025M sodium1-hexylsulfonate (pH 3):acetonitrile (condition C); and column: Luna C18(2) 100A, 250×4.6 mm (Serial number 599779-23), elution gradient system:a phosphate buffer solution (pH 3.0):methanol (condition D).

¹H NMR spectra were registered on Bruker AMX-400 (German) spectrometers.

High-resolution mass-spectra were obtained on a time-of-flight-assistedmass-spectrometer by the method of matrix laser-desorption ionizationwith 2,5-dihydroxybensoic acid used as a matrix, on an Ultraflex massspectrometer (“Bruker”, German).

Example 1 Preparation of1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione (compound 1)

2-(Imidazol-4-yl)-ethanamide of pentandioic-1,5 acid (1 g; 4.4 mmol)dissolved in 5 ml of acetic acid was filled in a flat-bottom flask. Oneand half equivalents of acetylchloride were added dropwise. The reactionmass was allowed to stand for 12 hours under stirring at 90° C. Thereaction was controlled by ¹H-NMR spectroscopy. The reaction mixture wascooled, and the solvent was removed under vacuum. The formed residue wasdissolved in the minimum amount of water, and sodium carbonate was addedbatchwise under stirring to reach the pH value of 8-9. The precipitatewas filtered and washed with a small amount of water, and dried. Afterfiltration, the stock solution was extracted three rimes with methylenechloride. The combined stock solution was dried over sodium sulfate, andthe solvent was removed under vacuum. The formed residue was dried,combined with the first portion (after filtration), and a the amount ofthe obtained 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione in theform of a light powder was 0.52 g (yield, 56%). LC/MS, an individualpeak at a retention time of 1.57 min, [M+H]⁺=208, ¹H-NMR (CD₃OD), δ,m.d.: 1.87-1.93 (m, 2H, 4′-CH₂), 2.61-2.65 (t, 4H, 3′,5′-CH₂), 2.76-2.80(t, 2H, 1-CH₂), 3.96-4.00 (t, 2H, 2-CH₂), 6.8 (s, 1H, 5″-CH-Im), 7.55(s, 1H, 2″-CH-Im).

Example 2 Preparation of1-(2-1H-imidazol-4-yl)ethyl)piperidine-2,6-dione (compound 1)

2-(Imidazol-4-yl)-ethanamide of pentandioic-1,5 acid (1 g; 4.4 mmol) and10 ml of propionic anhydride were filled in a flat-bottom flask. Threeequivalents of sodium acetate were added, and the mixture was allowed tostand under stirring at 120° C. for 12 hours. The reaction wascontrolled by ¹H-NMR spectroscopy. The reaction mixture was diluted witha three-fold excess of water under cooling and stirring, and sodiumcarbonate was added batchwise to reach the pH value of 8-9. The reactionmixture was extracted with ethyl acetate three times. A combined organicstock solution was dried over sodium sulfate, and the solvent wasremoved. The amount of the obtained1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-ione in the form of lightyellow crystals was 0.37 g (yield, 40%). [M]⁺207.9. ¹H-NMR (CD₃OD), δ,m.d.: 1.85-1.91 (m, 2H, 4′-CH₂), 2.60-2.63 (t, 4H, 3′,5′-CH₂), 2.73-2.77(t, 2H, 1-CH₂), 3.95-4.00 (t, 2H, 2-CH₂), 6.8 (s, 1H, 5″-CH-Im), 7.52(s, 1H, 2″-CH-Im).

Example 3 Preparation of1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione (compound 1)

2-(Imidazol-4-yl)-ethanamide of pentandioic-1,5 acid (100 g, 0.44 mol),80 ml (0.85 mol) acetic anhydride (80 ml, 0.85 mol) and toluene (200 ml)were added to 1 L cone flask equipped with a reflux condenser. Theobtained suspension was heated until the solid was dissolved, and thesolution was refluxed for 6 to 8 hours. The solvent was removed undervacuum, and 300 ml of methanol were added to the resulting oil, and thesolvent was repeatedly removed under vacuum. The residue was dissolvedin 300 ml of methylene chloride and 65 ml of triethylamine were addedthereto. The resulting solution was concentrated under vacuum andallowed to stand for 18 hours at +4° C. The residue was filtered througha Buchner funnel (d=10 cm), washed three times with isopropanol, anddried at +70° C. The degree of purity was controlled by a TLC method(Rf_(product), 0.54; (1)). In case of a need for additional purificationand clarification, the product was recrystallized, and a hot solution ofthe product was simultaneously treated with carbon black/carbon. Theamount of the obtained 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dionewas 73.6 g (yield, 80%). [M+H]⁺=208, ¹H-NMR (CD₃OD), δ, m.d.: 1.87-1.93(m, 2H, 4′-CH₂), 2.61-2.65 (t, 4H, 3′,5′-CH₂), 2.76-2.80 (t, 2H, 1-CH₂),3.96-4.00 (t, 2H, 2-CH₂), 6.8 (s, 1H, 5″-CH-Im), 7.55 (s, 1H, 2″-CH-Im).

The following compounds were prepared by the above-disclosed method:

Number of a com- pound Structural formula Physical and chemical data  4

LC/MS: an individual peak at a retention time of 1.0 min, [M + H]⁺ =211. HPLC under condition A: an individual peak at a retention time of10.9 min 11

LC/MS: an individual peak at a retention time of 1.08 min, [M + H]⁺ =220. HPLC under condition A: an individual peak at a retention time of17.5 min

Example 4 Preparation of1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione (compound 1)

Glutaric anhydride (3.5 g, 0.031 mol) was added to2-(imidazol-4-yl)-ethanamide of pentandioic-1,5 acid (4.5 g; 0.020 mol)dissolved under heating in 25 ml of N,N′-formamide, and the reactionmixture was heated to 100° C. for 4-6 hours. The completeness of thereaction was checked by a TLC or electrophoresis method. The solvent wasremoved under vacuum, the oil-like residue was dissolved in 50 ml ofwater, and the solution was passed through a column filled with 70 ml ofAmberlite IRA-96. The eluate comprising the target compound wascollected, and the solvent was removed under vacuum. The resulting solidresidue was recrystallized from chloroform. The amount of the obtained1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione was 3.1 g (75.6%).

Rf 0.43 (2). [M]⁺ 207.9.

¹H-NMR (CD₃OD), δ, m.d.: 1.87-1.93 (m, 2H, 4′-CH₂), 2.61-2.65 (t, 4H,3′,5′-CH₂), 2.76-2.80 (t, 2H, 1-CH₂), 3.96-4.00 (t, 2H, 2-CH₂), 6.8 (s,1H, 5″-CH-Im), 7.55 (s, 1H, 2″-CH-Im).

HPLC under condition A: an individual peak at a retention time of 15.5min.

Fourier-IR spectrum (in a KBr table, ν, cm⁻¹): 3136, 3070, 2833(—NH-val.), 1720, 1670 (CO, cycl. imide), 1339, 1257 (—CH₂—). Found, %:S, 57.60; H, 6.12; N, 21.17. C₁₀H₁₃N₃O₂. Calculated, %: S, 57.96; H,6.32; N, 20.28.

Example 5 Preparation of1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione (compound 1)

2-(Imidazol-4-yl)-ethanamide of pentandioic-1,5 acid (100 g, 0.44 mol),propionic anhydride (102 ml, 0.80 mol) and toluene (200 ml) were addedto 1 L cone flask equipped with a reflux condenser. The obtainedsuspension was heated until the solid is dissolved, and the solution wasrefluxed for 8 to 9 hours. The solvent was removed under vacuum, and 300ml of methanol were added to the resulting oil, and the solvent wasrepeatedly removed under vacuum. The residue was dissolved in 300 ml ofmethylene chloride and 65 ml of triethylamine were added thereto. Theresulting solution was concentrated under vacuum to evaporate of about70% of methylene chloride and then was allowed to stand for 18 hours at0 to +4° C. The residue was filtered, washed three times withisopropanol cooled to from 0 to −5° C. The crude product wasrecrystallized, and a hot solution of the product was simultaneouslytreated with carbon black/carbon. The degree of purity was controlled bya TLC method (Rf_(product), 0.54; (1)). The solution of the product wassubjected to a hot filtration on a “MILLIPORE” filtration system (0.45μm), and dried under vacuum in a drying oven at +70° C. The amount ofthe obtained 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione was 60.0g, yield-65%. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.81 (m, 2H,CH₂CH₂CH₂); 2.58 (m, 6H, CH₂C, CH₂CH₂CH₂); 3.83 (t, 2H, CH₂N, J=7.8 Hz);6.77 (bs, 1H, CCH) 7.48 (bs, 1H, NCHN); 11.8 (bs, 1H, NH).

Example 6 Preparation of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2-dione(compound 1)

N^(β)-Glutarylhistamine (5.0 g; 0.022 mol) was heated in 12 ml of aceticanhydride to 100° C. for 4-6 hours. The completeness of the reaction waschecked by a TLC or electrophoresis method. The solvent was removed fromthe reaction mixture under vacuum, and the resulting solid residue wasrecrystallized from isopropanol alcohol. The amount of the obtained1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione was 3.7 g (80%). Rf0.43 (2). Found %: C 57.73; H 6.15; N 20.17. C₁₀H₁₃N₃O₂. Calculated %:S, 57.96; H, 6.32; N, 20.28.

Example 7 1-[2-(1H-benzothiazol-2-yl)ethyl]piperidine-2-dione (compound7)

A mixture of 5-{[2-(1,3-benzothiazol-2-yl)ethyl]amino}-5-oxopentanoicacid (22 g; 0.075 mol) and acetic anhydride (23 g; 0.225 mol) wereboiled in 150 ml of dioxane for 3 hours. Dioxane was removed undervacuum, 200 ml of water was added and the mixture was neutralized with30% sodium hydroxide to neutral pH. The precipitated oil was trituratedin crystals. The residue was purified by chromatography (SiCO₂ 60-100μm, eluent: ethylacetate-hexane (1:1)). The amount of the obtained1-[2-(1H-imidazol-2-yl)ethyl]piperidine-2,6-dione was 16.5 g (79.9%).LC/MS: an individual peak at a retention time of 2.26 min, [M+H]⁺=275.HPLC under condition A: an individual peak at a retention time of 9.34min. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.85 (quint, 2H,CH₂CH₂CH₂, J=6.8 Hz); 2.59 (t, 4H, CH₂CH₂CH₂, J=6.8 Hz); 3.24 (t, 2H,CH₂S, J=7.3 Hz); 4.08 (t, 2H, CH₂N, J=7.3 Hz); 7.43, 7.49 (t, 1H, Ar,J=7.6 Hz); 7.96, 8.04 (d, 1H, Ar, J=7.6 Hz).

The following compounds were prepared by the above-disclosed method:

Number of a com- pound Structural formula Physical and chemical data 6

LC/MS: an individual peak at a retention time of 1.43 min, [M + H]⁺ =225. HPLC under condition D: an individual peak at a retention time of31.28 min. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.82 (quint, 2H,CH₂CH₂CH₂, J = 6.5 Hz); 2.58 (t, 4H, CH₂CH₂CH₂, J = 6.5 Hz); 3.12 (t,2H, CH₂C, J = 7.4 Hz); 3.97 (t, 2H, CH₂N, J = 7.4 Hz); 7.58 (d, 1H, SCH,J = 3.2 Hz); 7.70 (d, 1H, NCH, J = 3.2 Hz) 8

LC/MS: an individual peak at a retention time of 0.41 min, [M + H]⁺ =208. HPLC under condition B: an individual peak at a retention time of16.72 min. ¹H-NMR (400.13 MHz, DMSO-d₆, m.d., J/Hz): 1.82 (quint, 2H,CH₂CH₂CH₂) J = 6.5 Hz); 2.57 (t, 4H, CH₂CH₂CH₂, J = 6.5 Hz); 2.72 (t,2H, CH₂C, J = 7.5 Hz); 3.90 (t, 2H, CH₂N, J = 7.5 Hz); 6.86 (s, 2H,CHN); 11.72 (bs, 1H, NH)

Example 8 1-[2-(1H-pyridyl-3-yl)ethyl]piperidine-2,6-dione (compound 10)

2-(pyridyl-3-yl)-ethanamide of pentandioic-1,5 acid (29.00 g; 0.12 mol)and anhydrous sodium acetate (5.9 g; 0.07 mol) were dissolved in 200 mlof acetic anhydride. The reaction mixture was heated to simmering andwas further refluxed for 18 hours. After completion of the reaction, thesolvent was removed under vacuum, and a residue was dissolved in 500 mlof dichloromethane, washed two times with 100 ml portions of a 3% sodasolution and dried over sodium sulfate. The solvent was removed undervacuum, and the resulting oil was dissolved in dioxane. A 3M HClsolution in dioxane was added, and the precipitate was filtered andrecrystallized from 125 g of isopropanol. The product in the form ofhydrochloride was obtained in an amount of 25 g (yield, 80%). LC/MS: anindividual peak at a retention time of 0.5 min, [M+H]⁺=218. HPLC undercondition D: an individual peak at a retention time of 16.72 min. ¹H-NMR(400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.78 (quint, 2H, CH₂CH₂CH₂, J=6.4Hz); 2.56 (t, 4H, CH₂CH₂CH₂, J=6.4 Hz); 2.73 (t, 2H, CH₂C, J=7.3 Hz);3.86 (t, 2H, CH₂N, J=7.3 Hz); 7.30 (dd, 1H, 5-Pyr, J=7.8, 4.5 Hz); 7.60(d, 1H, 4-Pyr, J=7.8 Hz); 8.37 (d, 1H, 2-Pyr, J=1.5 Hz); 8.41 (dd, 1H,6-Pyr, J=4.5, 1.5 Hz).

The following compounds were prepared by the above-disclosed method:

Number of Physical and a compound Structural formula chemical data 2

LC/MS: an individual peak at a retention time of 0.5 min, [M + H]⁺ =222. HPLC under condition D: an individual peak at a retention time of19.7 min. ¹H-NMR (400.13 MHz, DMSO- d₆, δ, m.d., J/Hz): 1.82 (quint, 2H,CH₂CH₂CH₂, J = 6.5 Hz); 2.58 (t, 4H, CH₂CH₂CH₂, J = 6.5 Hz); 3.12 (t,2H, CH₂C, J = 7.4 Hz); 3.97 (t, 2H, CH₂N, J = 7.4 Hz); 7.58 (d, 1H, SCH,J = 3.2 Hz); 7.70 (d, 1H, NCH, J = 3.2 Hz) 3

LC/MS: an individual peak at a retention time of 0.41 min, [M + H]⁺ =236. HPLC under condition D: an individual peak at a retention time of22.16 min. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 0.91 (s, 6H,CH₃); 2.58 (m, 6H, CH₂C, CH₂CCH₂); 3.86 (t, 2H, CH₂N, J = 7.3 Hz); 6.60,6.85 (bs, 1H, CCH); 7.50 (bs, 1H, NCHN); 11.8 (bs, 1H, NH) 5

LC/MS: an individual peak at a retention time of 0.21 min, [M + H]⁺ =222. HPLC under condition B: an individual peak at a retention time of20.7 min. ¹H-NMR (400.13 MHz, DMSO- d₆, δ, m.d., J/Hz): 1.82 (quint, 2H,CH₂CH₂CH₂, J = 6.4Hz); 2.53 (m, 2H, CH₂C); 2.58 (t, 4H, CH₂CH₂CH₂, J =6.4 Hz); 3.57 (s, 3H, NMe); 3.80 (t, 2H, CH₂N, J = 7.8 Hz); 6.85 (s, 1H,CCH); 7.42 (s, 1H, NCHN)

Example 9 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione (compound 1)

N,N′-dimethylformamide (60 ml) and 2-(imidazol-4-yl)-ethanamide ofpentandioic-1,5 acid (20 g) were filled in a flat-bottom flask (250 ml).Carbonyldiimidazole (17.3 g; 1.2 equiv.) was added under vigorousstirring. The reaction mixture was heated to 90° C. for 2 hours. Thereaction was controlled by ¹H-NMR spectroscopy (a sample (0.5 ml) wasdiluted with a sulphuric ether, and the precipitate was dissolved inDMSO-d₆). When the initial 2-(imidazol-4-yl)-ethanamide ofpentandioic-1,5 acid was absent in the reaction mass, the mass wascooled and poured out into a three-fold volume of methyl tert-butylether (180 ml). The reaction mixture was allowed to stand for 1 hour,and the precipitate was filtered, washed with 60 ml of methyl tert-butylether, and dried. The yield of the crude1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione was 12.4 g (67%).

The crude 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione (12 g) andisopropanol (36 mg) were filled in a 100 ml flat-bottom flask. Themixture was heated to complete dissolution of the residue, then 1.2 g ofactivated carbon were added, and the mixture was allowed to stand for anhour. The solution being hot was filtered through a pre-heated ceramicfilter. The residue on the filter was washed with 6 ml of hotisopropanol. The hot stock solution was cooled to room temperature andallowed to stand for a night under stirring for crystallization.Precipitated crystals were filtered, washed with 6 ml of coolisopropanol, and dried. After recrystallization, the amount of theobtained 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione was 10.1 g(84%). The product was analyzed with an LC/MS method: an individual peakat a retention time of 1.57 min; [M+H]⁺=208. ¹H-NMR (CD₃OD), δ, m.d.:1.87-1.93 (m, 2H, 4′-CH₂); 2.61-2.65 (t, 4H, 3′,5′-CH₂); 2.76-2.80 (t,2H, 1-CH₂); 3.96-4.00 (t, 2H, 2-CH₂); 6.8 (c, 1H, 5″-CH-Im); 7.55 (c,1H, 2″-CH-Im).

Compounds 9, 12-115 represented in Table 3 were synthesized by analogousmethods.

TABLE 3 Number of a compound Structural formula Constants  9

LC/MS: an individual peak at a retention time of 0.21 min, [M + H]⁺ =219. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.82 (quint, 2H,CH₂CH₂CH₂, J = 6.4 Hz); 2.58 (t, 4H, CH₂CH₂CH₂, J = 6.4 Hz); 3.08 (t,2H, CH₂C, J = 7.3 Hz); 3.96 (t, 2H, CH₂N, J = 7.3 Hz); 7.90 (d, 2H,3,5-Pyr, J = 7.8 Hz); 8.80 (d, 2H, 2,6-Pyr, J = 7.8 Hz) 12

LC/MS: an individual peak at a retention time of 0.21 min, [M + H]⁺ =224. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.79 (quint, 2H,COCH₂CH₂CH₂CO, J = 6.6 Hz), 2.58 (t, 4H, COCH₂CH₂CH₂CO, J = 6.6 Hz),2.72 (t, 2H, CH₂C, J = 7.8 Hz), 3.84 (t, 2H, CH₂N, J = 7.8 Hz), 6.97 (d,1H, 4- thiophene, J = 4.6 Hz), 7.20 (d, 1H, 2-thiophene, J = 3.1 Hz),7.45 (dd, 1H, 5- thiophene, J = 4.6, 3.1 Hz) 13

LC/MS: an individual peak at a retention time of 0.21 min, [M + H]⁺ =219. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.80 (quint, 2H,CH₂CH₂CH₂, J = 6.4 Hz); 2.55 (t, 4H, CH₂CH₂CH₂, J = 6.4 Hz); 3.20 (t,2H, CH₂C, J = 7.3 Hz); 4.0 (t, 2H, CH₂N, J = 7.3 Hz); 7.82 (t, 1H,4-Pyr, J = 4.5 Hz); 7.85 (d, 1H, 3-Pyr, J = 7.8 Hz); 8.41 (t, 1H, 5-Pyr,J = 1.5 Hz); 8.67 (d, 1H, 6-Pyr, J = 4.5 Hz). 14

LC/MS: an individual peak at a retention time of 0.21 min, [M + H]⁺ =225. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.3-1.4 (m, 6H,morph), 1.75 (quint, 2H, COCH₂CH₂CH₂CO, J = 6.6 Hz), 2.25 (m, 2H, CH₂N-morph), 2.3 (m, 4H, morph), 2.6 (t, 4H, COCH₂CH₂CH₂CO, J = 6.6 Hz), 3.7(m, 3H, CH₂N) 15

[M + H]⁺ = 273. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.82 (t, 2H, CCH₂CH₂N, J = 8.8 Hz); 3.89 (t, 2H, CCH₂CH₂N, J = 8.8 Hz);6.63 (d, 1H, Indole-6, J = 8.6 Hz); 6.75 (s, 1H, Indole-4); 7.16 (s, 1H,Indole-2); 7.43 (d, 1H, Indole-7, J = 8.6 Hz); 8.68 (bs, 1H, OH); 10.74(s, 1H, NH) 16

[M + H]⁺ = 210. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.73 (t, 2H, CCH₂CH₂N, J = 7.2 Hz); 3.34 (bs, 4H, NCH₂CH₂NH); 3.99 (t,2H, CCH₂CH₂N, J = 7.2 Hz); 5.70 (bs, 1H, NH) 17

[M + H]⁺ = 191. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.94 (t, 2H, CCH₂CH₂N, J = 7.2 Hz); 3.93 (t, 2H, CCH₂CH₂N, J = 7.2 Hz);6.91 (s, 1H, SCCH); 8.11 (s, 1H, SNCH) 18

[M + H]⁺ = 209. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.94 (t, 2H, CCH₂CH₂N, J = 7.2 Hz); 3.93 (t, 2H, CCH₂CH₂N, J = 7.2 Hz);7.76 (s, 1H, CNCH); 8.11 (s, 1H, CNHCH) 19

[M + H]⁺ = 210. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.20 (t, 2H, CCH₂CH₂N, J = 7.0 Hz); 3.93 (t, 2H, CCH₂CH₂N, J = 7.0 Hz);7.76 (s, 1H, CH) 20

LC/MS: an individual peak at a retention time of 0.21 min, [M + H]⁺ =236. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.14 (s, 6H, CH₃),1.73 (t, 2H, CH₂Me, J = 6.7 Hz), 2.59 (t, 2H, CH₂C, J = 7.5 Hz), 2.64(t, 2H, CH₂CO, J = 6.7 Hz), 3.83 (t, 2H, CH₂N, J = 7.5 Hz), 6.75 (s, 1H,CCH), 7.48 (s, 1H, NHN), 11.79 (s, 1H, COOH). 21

[M + H]⁺ = 315. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.65 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.09 (d, 2H, CCH₂CHN, J = 11.7 Hz); 3.67 (s, 3H, CH₃); 4.16 (t, 1H,NCHCH₂, J = 11.7 Hz); 6.99 (dd, 1H, Indole-5, J = 7.4 Hz, J = 7.7 Hz);7.04 (dd, 1H, Indole-6, J = 7.9 Hz, J = 7.4 Hz); 7.09 (s, 1H, Indole-2);7.31 (d, 1H, Indole-7, J = 7.9 Hz); 7.52 (d, 1H, Indole-4, J = 7.7 Hz);10.83 (s, 1H, NH) 22

[M + H]⁺ = 225. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.77 (dt,2H, CHCH₂CH₂NC, J = 8.5 Hz, J = 7.0 Hz); 1.84 (quint, 2H, CH₂CH₂CH₂, J =7.5 Hz); 2.05 (dt, 2H, CH₂CH₂CH₂N, J = 6.0 Hz, J = 8.3 Hz); 2.13 (m, 1H,CH); 2.26 (s, 3H, CH₃); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz); 3.01 (d,2H, CHCH₂NCH₃, J = 7.2 Hz); 3.06 (t, 2H, CH₂CH₂NCH₃, J = 8.3 Hz); 3.68(t, 2H, CHCH₂CH₂NC, J = 7.0 Hz) 23

LC/MS: an individual peak at a retention time of 0.21 min, [M + H]⁺ =211. ¹H-NMR (300.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.91 (m, 6H,COCH₂CH₂CH₂CO, NCH₂CH₂CH₂CH₂N), 2.65 (t, 4H, COCH₂CH₂CH₂CO, J = 6.5 Hz),2.99 (s, 2H, NCH₂), 3.24 (d, 2H, NCH₂, J = 5.1 Hz), 3.53 (s, 2H, NCH₂),3.96 (t, 2H, CONCH₂, J = 5.9 Hz), 10.80 (s, 1H, HCl), 24

LC/MS: an individual peak at a retention time of 0.21 min, [M + H]⁺ =222. ¹H-NMR (300.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84 (m, 4H,COCH₂CH₂CH₂CO, NCH₂CH₂CH₂N), 2.57 (m, 4H, COCH₂CH₂CH₂CO), 3.64 (t, 2H,NCH₂, J = 7.0 Hz), 3.94 (t, 2H, NCH₂, J = 7.0 Hz), 6.87 (s, 1H, CHN═);7.15 (s, 1H, CHN); 7.60 (s, 1H, NCHN) 25

[M + H]⁺ = 222. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.20 (t, 2H, CCH₂CH₂N, J = 7.0 Hz); 3.28 (s, 3H, CH₃); 3.93 (t, 2H,CCH₂CH₂N, J = 7.0 Hz); 6.70 (s, 1H, NCHC); 7.39 (s, 1H, NCHNCH₃) 26

[M + H]⁺ = 280. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.22 (t,3H, CH₃, J = 7.1 Hz); 1.84 (quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.56 (d,2H, NHCCH₂CHC, J = 12.1 Hz); 2.65 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz); 4.12(quint, 2H, COCH₂CH₃, J = 7.1 Hz); 4.16 (t, 1H, NCHCH₂C, J = 12.1 Hz);6.79 (s, 1H, NCHC); 8.03 (s, 1H, NCHNH); 8.26 (bs, 1H, NH) 27

[M + H]⁺ = 329. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.22 (t,3H, CH₃, J = 7.1 Hz); 1.84 (quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.65 (t,4H, CH₂CH₂CH₂, J = 7.5 Hz); 3.09 (d, 2H, CCH₂CHN, J = 11.7 Hz); 4.12(quint, 2H, COCH₂CH₃, J = 7.1 Hz); 4.16 (t, 1H, NCHCH₂C, J = 11.7 Hz);6.99 (dd, 1H, Indole-5, J = 7.4 Hz, J = 7.7 Hz); 7.04 (dd, 1H, Indole-6,J = 7.9 Hz, J = 7.4 Hz); 7.09 (s, 1H, Indole-2); 7.31 (d, 1H, Indole-7,J = 7.9 Hz); 7.52 (d, 1H, Indole-4, J = 7.7 Hz); 10.83 (s, 1H, NH) 28

[M + H]⁺ = 224. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 2.54 (d,4H, C(O)CH₂CHOH, J = 7.5 Hz); 3.20 (t, 2H, CCH₂CH₂N, J = 7.0 Hz); 3.93(t, 3H, CCH₂CH₂N, J = 7.0 Hz); 3.94 (t, 1H, NCCH₂CHOH, J = 7.5 Hz); 5.24(bs, 1H, OH); 6.86 (s, 1H, NCHC); 7.61 (s, 1H, NCHNH); 8.24 (bs, 1H, NH)29

[M + H]⁺ = 224. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.67 (dt,2H, CH₂CHOH, J = 8.4 Hz, J = 12.5 Hz); 2.48 (t, 2H, CH₂CH₂CHOH, J = 12.5Hz); 3.20 (t, 2H, CCH₂CH₂N, J = 7.0 Hz); 3.93 (t, 2H, CCH₂CH₂NC, J = 7.0Hz); 4.60 (t, 1H, CHOH, J = 8.4 Hz); 5.38 (bs, 1H, OH); 6.86 (s, 1H,NCHC); 7.61 (s, 1H, NCHNH); 8.24 (s, 1H, NH) 30

LC/MS: an individual peak at a retention time of 0.21 min, [M + H]⁺ =208. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.78 (quint, 2H,COCH₂CH₂CH₂CO, J = 6.4 Hz), 2.55 (t, 4H, COCH₂CH₂CH₂CO, J = 6.5 Hz),3.94 (t, 2H, CH₂N, J = 6.1 Hz), 4.05 (t, 2H, CH₂N, J = 6.1 Hz), 6.82 (s,1H, CHN═); 7.09 (s, 1H, CHN); 7.54 (s, 1H, NCHN) 31

[M + H]⁺ = 284. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.20 (t, 2H, CCH₂CH₂N, J = 7.0 Hz); 3.93 (t, 2H, CCH₂CH₂N, J = 7.0 Hz);7.23 (d, 1H, p-Ph, J = 7.4 Hz); 7.39 (dd, 2H, m-Ph, J = 7.6 Hz, J = 7.4Hz); 7.70 (d, 2H, o-Ph, J = 7.6 Hz); 8.03 (s, 1H, NCHNH); 8.50 (s, 1H,NH) 32

[M + H]⁺ = 222. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.16 (d,3H, CH₃, J = 7.0 Hz); 1.84 (quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.63 (t,4H, CH₂CH₂CH₂, J = 7.5 Hz); 3.14 (d, 2H, CCH₂CHCH₃, J = 9.5 Hz); 3.94(quint, 1H, CH₂CNCHCH₃, J = 7.0 Hz, J = 9.5 Hz); 6.87 (s, 1H, NCHC);7.81 (s, 1H, NCHNH); 8.24 (s, 1H, NH) 33

[M + H]⁺ = 222. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.16 (d,3H, CH₃, J = 7.0 Hz); 1.84 (quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.63 (t,4H, CH₂CH₂CH₂, J = 7.5 Hz); 3.14 (d, 2H, CCH₂CHN, J = 9.5 Hz); 3.94(quint, 1H, CCH₂CHN, J = 7.0 Hz, J = 9.5 Hz); 6.87 (s, 1H, CCHN); 7.81(s, 1H, NCHNH); 8.24 (s, 1H, NH) 34

[M + H]⁺ = 209. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.20 (t, 2H, CCH₂CH₂N, J = 7.0 Hz); 3.93 (t, 2H, CCH₂CH₂N, J = 7.0 Hz);7.95 (s, 1H, OCHC); 8.84 (s, 1H, OCHNC) 35

LC/MS: an individual peak at a retention time of 0.21 min, [M + H]⁺ =209. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.82 (quint, 2H,COCH₂CH₂CH₂CO, J = 6.5 Hz), 2.58 (t, 4H, COCH₂CH₂CH₂CO, J = 6.5 Hz),2.79 (t, 2H, CH₂C, J = 7.6 Hz), 3.87 (t, 2H, CH₂N, J = 7.6 Hz), 7.59 (s,1H, CHN═) 36

LC/MS: an individual peak at a retention time of 0.21 min, [M + H]⁺ =210. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.83 (quint, 2H,COCH₂CH₂CH₂CO, J = 6.5 Hz), 2.57 (t, 4H, COCH₂CH₂CH₂CO, J = 6.5 Hz),3.04 (t, 2H, CH₂C, J = 7.2 Hz), 3.95 (t, 2H, CH₂N, J = 7.2 Hz), 16.09(s, 1H, NH) 37

[M + H]⁺ = 242. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.51 (t, 2H, CCH₂CH₂N, J = 8.1 Hz);2.68 (t, 4H, CCH₂CH₂CH₂, J = 7.5 Hz); 3.89 (t, 2H, CCH₂CH₂N, J = 8.1Hz); 7.33 (d, 1H, CCHCHC, J = 8.3 Hz); 7.58 (s, 1H, NCCHC); 8.11 (d, 1H,SCCHCHC, J = 8.3 Hz) 38

[M + H]⁺ = 259. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.95 (t, 2H, CCH₂CH₂N, J = 8.1 Hz); 3.89 (t, 2H, CCH₂CH₂N, J = 8.1 Hz);7.14 (d, 1H, CHCCH₂CH₂N, J = 7.5 Hz); 7.23 (dd, 1H, CHCHCH, J = 7.5 Hz,J = 8.2 Hz); 8.07 (d, 1H, NCCH, J = 8.2 Hz); 15.40 (bs, 1H, NH) 39

[M + H]⁺ = 259. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.51 (t, 2H, CCH₂CH₂N, J = 8.1 Hz);2.68 (t, 4H, CCH₂CH₂CH₂, J = 7.5 Hz); 3.40 (s, 1H, NH); 3.89 (t, 2H,CCH₂CH₂N, J = 8.1 Hz); 7.33 (d, 1H, NHCCHCHC, J = 8.1 Hz); 7.58 (s, 1H,NCCHC); 8.31 (d, 1H, NHCCHCHC, J = 8.1 Hz) 40

[M + H]⁺ = 243. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.20 (t, 2H, CCH₂CH₂N, J = 7.0 Hz); 3.93 (t, 2H, CCH₂CH₂N, J = 7.0 Hz);8.43 (s, 1H, NCHN); 9.31 (s, 1H, SCHN) 41

[M + H]⁺ = 258. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.95 (t, 2H, CCH₂CH₂N, J = 8.1 Hz); 3.89 (t, 2H, CCH₂CH₂N, J = 8.1 Hz);6.88 (t, 1H, NNCHCHCH, J = 6.9 Hz); 7.43 (dd, 1H, NNCHCHCH, J = 6.8 Hz,J = 8.9 Hz); 7.63 (s, 1H, NCHC); 7.80 (d, 1H, NNCCH, J = 8.9 Hz); 8.71(d, 1H, NNCHCHCH, J = 6.9 Hz) 42

[M + H]⁺ = 258. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.82 (t, 2H, CCH₂CH₂NC, J = 8.8 Hz); 3.89 (t, 2H, CCH₂CH₂NC, J = 8.8Hz); 7.15 (s, 1H, Indole-2); 7.61 (dd, 1H, Indole-5, J = 5.6 Hz, J = 8.1Hz); 8.11 (d, 1H, Indole-4, J = 8.1 Hz); 8.45 (d, 1H, Indole-6, J = 5.6Hz); 12.28 (s, 1H, NH) 43

[M + H]⁺ = 258. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.20 (t, 2H, CCH₂CH₂N, J = 7.0 Hz); 3.93 (t, 2H, CCH₂CH₂NC, J = 7.0 Hz);6.87 (s, 1H, NCHC); 7.13 (dd, 1H, NCHCH, J = 7.0 Hz, J = 6.8 Hz); 7.46(dd, 1H, NCCHCH, J = 6.8 Hz, J = 9.0 Hz); 7.66 (d, 1H, NCCHCH, J = 9.0Hz); 8.57 (d, 1H, CH₂CNCHCH, J = 7.0 Hz) 44

[M + H]⁺ = 252. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.65 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.09 (d, 2H, CCH₂CHCOOH, J = 11.7 Hz); 4.16 (t, 1H, NCHCH₂, J = 11.7Hz); 6.35 (s, 1H, OCHCHC); 7.41 (s, 1H, OCHC); 7.53 (s, 1H, OCHCHC);10.01 (s, 1H, OH) 45

LC/MS: an individual peak at a retention time of 1.07 min, [M]⁺ = 285.¹H-NMR (D₆-DMSO, 400 MHz) δ_(H), 1.79-1.88 (m, 2H, CH₂CH₂CH₂), 2.57 (t,J = 6.4 Hz, 4H, CH₂CH₂CH₂), 2.90 (t, J = 8.0 Hz, 2H, CH₂CH₂N), 3.98 (t,J = 8.0 Hz, 2H, CH₂CH₂N), 7.46 (dd, J = 8.0, 4.8 Hz, 1H, CCHCHCHNCH),8.27 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H, CCHCHCHNCH), 8.58 (dd, J = 4.8, 1.6Hz, 1H, CCHCHCHNCH), 9.13 (d, J = 2.4 Hz, 1H, CCHCHCHNCH), 13.88 (bs,1H, NH(triazole)). 46

LC/MS: an individual peak at a retention time of 0.97 min, [M + H]⁺ =265. ¹H-NMR (D₆-DMSO, 400 MHz) δ_(H), 1.77-1.84 (m, 2H, CH₂CH₂CH₂), 1.93(s, CH₃), 2.54 (t, J = 6.4 Hz, 4H, CH₂CH₂CH₂), 3.97 (t, J = 6.4 Hz, 2H,NCH₂CH₂N), 4.04 (t, J = 6.4 Hz, 2H, NCH₂CH₂N), 6.37 (d, J = 1.6 Hz, 1H,CH(pyrazole)), 7.47 (d, J = 1.6 Hz, 1H, CH(pyrazole)), 10.20 (bs, 1H,NH) 47

LC/MS: an individual peak at a retention time of 1.56 min, [M + H]⁺ =281. ¹H-NMR (D₆-DMSO, 400 MHz) δ_(H), 1.25 (s, 9H, C(CH₃)₃), 1.77-1.84(m, 2H, CH₂CH₂CH₂), 2.56 (t, J = 6.4 Hz, 4H, CH₂CH₂CH₂), 3.06 (t, J =7.2 Hz, 2H, CH₂CH₂CH₂), 3.95 (t, J = 7.2 Hz, 2H, CH₂CH₂N), 7.04 (s, 1H,CH(thiazole)). 48

LC/MS: an individual peak at a retention time of 1.16 min, [M + H]⁺ =250. ¹H-NMR (D₆-DMSO, 400 MHz) δ_(H), 1.74-1.82 (m, 2H, CH₂CH₂CH₂), 2.03(s, 3H, CCH₃), 2.11 (s, 3H, CCH₃), 2.38 (t, J = 8.0 Hz, 2H, CH₂CH₂N),2.56 (t, J = 6.4 Hz, 4H, CH₂CH₂CH₂), 3.57 (s, 3H, NCH₃), 3.59 (t, J =8.0 Hz, 2H, CH₂CH₂N). 49

LC/MS: an individual peak at a retention time of 1.71 min, [M + H]⁺ =285. ¹H-NMR (D₆-DMSO, 400 MHz) δ_(H), 1.71-1.79 (m, 2H, CH₂CH₂CH₂), 2.34(s, 3H, CCH₃), 2.56 (t, J = 6.4 Hz, 4H, CH₂CH₂CH₂), 2.77 (t, J = 8.0 Hz,2H, CH₂CH₂N), 3.62 (s, 3H, NCH₃), 3.75 (t, J = 8.0 Hz, 2H, CH₂CH₂N),6.97 (t, J = 8.0 Hz, 1H, C₆H₄), 7.04 (t, J = 8.0 Hz, 1H, C₆H₄), 7.30 (d,J = 8.0 Hz, 1H, C₆H₄), 7.48 (d, J = 8.0 Hz, 1H, C₆H₄). 50

LC/MS: an individual peak at a retention time of 1.15 min, [M + H]⁺ =284. ¹H-NMR (D₆-DMSO, 400 MHz) δ_(H), 1.77-1.84 (m, 2H, CH₂CH₂CH₂), 2.59(t, J = 6.4 Hz, 4H, CH₂CH₂CH₂), 2.64 (t, J = 8.0 Hz, 2H, CH₂CH₂N), 3.85(t, J = 8.0 Hz, 2H, CH₂CH₂N), 7.25 (t, J = 8.0 Hz, 1H, CH(Ph)), 7.45 (t,J = 8.0 Hz, 2H, CH(Ph)), 7.55 (s, 1H, CH(pyrazole)), 7.77 (d, J = 8.0Hz, 2H, CH(Ph)), 8.28 (s, 1H, CH(pyrazole)). 51

LC/MS: an individual peak at a retention time of 1.01 min, [M + H]⁺ =272. ¹H-NMR (D₆-DMSO, 400 MHz) δ_(H), 1.78-1.86 (m, 2H, CH₂CH₂CH₂), 2.56(t, J = 6.4 Hz, 4H, CH₂CH₂CH₂), 3.01 (t, J = 8.0 Hz, 2H, CH₂CH₂N), 3.74(s, 3H, CH₃), 4.05 (t, J = 8.0 Hz, 2H, CH₂CH₂N), 7.13 (t, J = 8.0 Hz,1H, C₆H₄), 7.18 (t, J = 8.0 Hz, 1H, C₆H₄), 7.45 (d, J = 8.0 Hz, 1H,C₆H₄), 7.52 (d, J = 8.0 Hz, 1H, C₆H₄). 52

LC/MS: an individual peak at a retention time of 1.24 min, [M + H]⁺ =286. ¹H-NMR (D₆-DMSO, 400 MHz) δ_(H), 1.79-1.87 (m, 2H, CH₂CH₂CH₂), 2.58(t, J = 6.4 Hz, 4H, CH₂CH₂CH₂), 3.16 (t, J = 7.2 Hz, 2H, CH₂CH₂N), 4.07(t, J = 7.2 Hz, 2H, CH₂CH₂N), 7.51- 7.58 (m, 3H, CH(Ph)), 7.97 (dd, J =8.0, 1.6 Hz, 2H, CH(Ph)). 53

LC/MS: an individual peak at a retention time of 0.94 min, [M + H]⁺ =209. ¹H-NMR (D₆-DMSO, 400 MHz) δ_(H), 1.76-1.83 (m, 2H, CH₂CH₂CH₂), 2.53(t, J = 6.4 Hz, 4H, CH₂CH₂CH₂), 4.00 (t, J = 6.4 Hz, 2H, NCH₂CH₂N), 4.27(t, J = 6.4 Hz, 2H, NCH₂CH₂N), 7.86 (s, 1H, CH(triazole)), 8.43 (s, 1H,CH(triazole)). 54

[M + H]⁺ = 255. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.82 (t, 2H, CCH₂CH₂N, J = 8.8 Hz); 3.89 (t, 2H, CCH₂CH₂N, J = 8.8 Hz);6.91 (d, 1H, Indole-6, J = 9.0 Hz); 7.16 (s, 1H, NHCHC); 7.22 (s, 1H,Indole-4); 7.34 (d, 1H, Indole-7, J = 9.0 Hz); 10.75 (s, 1H, NH) 55

[M + H]⁺ = 225. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.60 (dt,2H, CHCH₂CH₂NC, J = 7.3 Hz, J = 7.1 Hz); 1.83 (t, 2H, CH₃NCH₂CH₂CH₂, J =6.4 Hz); 1.84 (quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.06 (m, 2H,CH₂CHCH₂CH₂N); 2.36 (s, 3H, CH₃); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.06 (t, 2H, CH₃NCH₂, J = 6.4 Hz); 3.44 (quint, 1H, CH, J = 7.0 Hz);3.68 (t, 2H, CHCH₂CH₂NC, J = 7.1 Hz) 56

[M + H]⁺ = 222. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.03 (d,3H, CH₃, J = 6.7 Hz); 1.69 (dt, 2H, CH₂CH₂CHCH₃, J = 8.5 Hz, J = 7.5Hz); 2.12 (tq, 1H, CNCCHCH₃, J = 8.5 Hz, J = 6.7 Hz); 2.54 (t, 2H,CH₂CH₂CHCH₃, J = 7.5 Hz); 3.20 (t, 2H, CCH₂CH₂NC, J = 7.0 Hz); 3.93 (t,2H, CCH₂CH₂NC, J = 7.0 Hz); 6.86 (s, 1H, NHCHC); 7.56 (s, 1H, NH); 7.61(s, 1H, NCHNH) 57

[M + H]⁺ = 210. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.60 (dt,2H, NCHCH₂CH₂N, J = 11.2 Hz, J = 8.0 Hz); 1.84 (quint, 2H, CH₂CH₂CH₂, J= 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz); 3.67 (d, 1H, NCHCH₂NH, J= 7.5 Hz); 3.68 (t, 1H, NCHCH₂CH₂N, J = 8.0 Hz); 4.05 (tt, 1H,NCHCH₂CH₂N, J = 7.5 Hz, J = 11.2 Hz); 8.31 (s, 1H, NCH); 8.73 (s, 1H,NH) 58

[M + H]⁺ = 260. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CCH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CCH₂CH₂CH₂, J = 7.5Hz); 2.94 (t, 2H, CCH₂CH₂NC, J = 7.2 Hz); 3.93 (t, 2H, CCH₂CH₂NC, J =7.2 Hz); 8.90 (s, 1H, NCHN); 9.08 (s, 1H, NCHC); 13.60 (s, 1H, NH) 59

[M + H]⁺ = 260. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.20 (t, 2H, CCH₂CH₂NC, J = 7.0 Hz); 3.93 (t, 2H, CCH₂CH₂NC, J = 7.0Hz); 8.55 (s, 1H, NHCHN); 8.79 (s, 1H, NCHNC); 12.91 (s, 1H, NH) 60

[M + H]⁺ = 260. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.94 (t, 2H, CCH₂CH₂NC, J = 7.2 Hz); 3.93 (t, 2H, CCH₂CH₂NC, J = 7.2Hz); 8.67 (s, 1H, NHCHN); 8.95 (s, 1H, NHCCHNC); 12.55 (s, 1H, NH) 61

[M + H]⁺ = 272. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CCH₂CH₂CH₂, J = 7.5Hz); 2.94 (t, 2H, NCH₂CH₂CN, J = 7.2 Hz); 3.93 (t, 2H, NCH₂CH₂CN, J =7.2 Hz); 8.94 (s, 2H, NCHCHN); 8.95 (s, 1H, NCHCCN); 8.98 (s, 1H,NCHCHN) 62

[M + H]⁺ = 272. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.20 (t, 2H, NCH₂CH₂CN, J = 7.0 Hz); 3.93 (t, 2H, NCH₂CH₂CN, J = 7.0Hz); 8.75 (s, 1H, CCHN); 8.90 (s, 1H, NCHN); 9.08 (s, 1H, NCCCHN) 63

[M + H]⁺ = 272. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.20 (t, 2H, NCH₂CH₂CN, J = 7.0 Hz); 3.93 (t, 2H, NCH₂CH₂CN, J = 7.0Hz); 8.60 (s, 1H, NCNCHCH); 8.79 (s, 1H, CNCHN); 8.98 (s, 1H, NCNCHCH)64

[M + H]⁺ = 191. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.95 (t, 2H, CCH₂CH₂NC, J = 6.6 Hz); 3.89 (t, 2H, CCH₂CH₂NC, J = 6.6Hz); 7.72 (s, 1H, SCHC); 8.11 (s, 1H, NCHC) 65

[M + H]⁺ = 223. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 2.53 (d,4H, CCH₂CHNH₂, J = 7.5 Hz); 3.20 (t, 2H, CCH₂CH₂NC, J = 7.0 Hz); 3.89(t, 1H, NCCH₂CHNH₂); 3.91 (bs, 2H, NH₂); 3.93 (t, 2H, CCH₂CH₂NC, J = 7.0Hz); 6.86 (s, 1H, NHCHC); 7.56 (bs, 1H, NH); 7.61 (s, 1H, NCHNH) 66

[M + H]⁺ = 251. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.53 (s,5H, CHCHCH₂CH₂N); 1.54 (q, 4H, NCH₂CH₂CH, J = 8.3 Hz); 1.77 (td, 2H,CHCH₂CH₂N, J = 7.0 Hz, J = 6.0 Hz); 1.84 (quint, 2H, CCH₂CH₂CH₂, J = 7.5Hz); 2.04 (m, 1H, CH₂CHCH₂CH₂N); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.76 (d, 2H, NCH₂CHCH₂CH₂N, J = 8.2 Hz); 2.97 (t, 4H, NCH₂CH₂CHCH, J =8.3 Hz); 3.68 (t, 2H, CH₂CHCH₂CH₂N, J = 7.0 Hz) 67

[M + H]⁺ = 223. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.70 (dt,2H, CH₂CH₂CHNH₂, J = 12.0 Hz, J = 12.5 Hz); 2.48 (t, 2H, CH₂CH₂CHNH₂, J= 12.5 Hz); 3.20 (t, 2H, CCH₂CH₂NC, J = 7.0 Hz); 3.93 (t, 2H, CCH₂CH₂NC,J = 7.0 Hz); 3.97 (s, 2H, NH₂); 5.98 (t, 1H, CNCCHNH₂, J = 12.0 Hz);6.86 (s, 1H, NCHC); 7.61 (s, 1H, NCHNH); 8.24 (s, 1H, NH) 68

[M + H]⁺ = 279. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.01 (s,6H, CH₃); 2.52 (s, 4H, CH₂CCH₂); 3.20 (t, 2H, CCH₂CH₂NC, J = 7.0 Hz);4.15 (t, 1H, CCH₂CHNC, J = 7.0 Hz); 6.86 (s, 1H, NCHC); 7.61 (s, 1H,NCHNH); 8.24 (s, 1H, NH); 10.01 (s, 1H, OH) 69

[M + H]⁺ = 279. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 0.85 (s,3H, CH₃); 1.19 (s, 3H, CH₃); 1.69 (t, 2H, CH₂CH₂CCH₃, J = 7.5 Hz); 2.48(t, 2H, CH₂CH₂CCH₃, J = 7.5 Hz); 3.20 (t, 2H, CCH₂CH₂N, J = 7.0 Hz);4.15 (t, 1H, CCH₂CHNC, J = 7.0 Hz); 6.86 (s, 1H, NCHC); 7.61 (s, 1H,NCHNH); 8.24 (s, 1H, NH); 10.01 (s, 1H, OH) 70

[M + H]⁺ = 266. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.03 (d,3H, CH₃, J = 6.7 Hz); 1.69 (dt, 2H, CH₂CH₂CHCH₃, J = 8.5 Hz, J = 7.5Hz); 2.12 (tq, 1H, CCHCH₃, J = 8.5 Hz, J = 6.7 Hz); 2.54 (t, 2H,CH₂CNCHC, J = 7.5 Hz); 2.56 (d, 2H, CCH₂CHCOH, J = 12.1 Hz); 4.16 (t,1H, CH₂CNCHC, J = 12.1 Hz); 6.79 (s, 1H, NCHC); 8.03 (s, 1H, NCHNH);8.26 (s, 1H, NH); 10.01 (s, 1H, OH) 71

[M + H]⁺ = 266. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 0.86 (d,3H, CH₃, J = 6.2 Hz); 1.90 (m, 1H, NCCH₂CHCH₃); 2.52 (d, 4H, CH₂CHCH₂, J= 7.5 Hz); 2.56 (d, 2H, CCH₂CHCOOH, J = 12.1 Hz); 4.16 (t, 1H, CNCHCOH,J = 12.1 Hz); 6.79 (s, 1H, NCHC); 8.03 (s, 1H, NCHNH); 8.26 (s, 1H, NH);10.01 (s, 1H, OH) 72

[M + H]⁺ = 252. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84 (t,2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz); 3.20(s, 2H, CCH₂CH₂N); 3.93 (s, 2H, CCH₂CH₂N); 8.03 (s, 1H, CH); 8.50 (s,1H, NH); 11.18 (bs, 1H, OH) 73

[M + H]⁺ = 222. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.47 (s, 3H, CH₃); 2.68 (t, 4H,CH₂CH₂CH₂, J = 7.5 Hz); 3.20 (t, 2H, CCH₂CH₂NC, J = 7.0 Hz); 3.93 (t,2H, CCH₂CH₂NC, J = 7.0 Hz); 6.45 (s, 1H, CH); 11.70 (s, 1H, NH) 74

[M + H]⁺ = 284. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.20 (t, 2H, CCH₂CH₂NC, J = 7.0 Hz); 3.93 (t, 2H, CCH₂CH₂NC, J = 7.0Hz); 6.87 (s, 1H, NCHC); 7.60 (dd, 2H, m-Ph, J = 7.8 Hz, J = 7.4 Hz);7.62 (d, 1H, p-Ph, J = 7.4 Hz); 8.31 (d, 2H, o-Ph, J = 7.8 Hz); 11.45(s, 1H, NH) 75

[M + H]⁺ = 267. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.70 (m,2H, CH₂CH₂CHNH₂); 2.48 (t, 2H, CH₂CNCHC, J = 12.5 Hz); 2.56 (d, 2H,CCH₂CHCOOH, J = 12.1 Hz); 3.97 (s, 2H, NH₂); 4.16 (t, 1H, CH₂CNCHC, J =12.1 Hz); 5.98 (t, 1H, CNCCHNH₂, J = 12.0 Hz); 6.79 (s, 1H, NHCHC); 7.56(s, 1H, NH); 8.03 (s, 1H, NCHNH); 10.01 (s, 1H, OH) 76

[M + H]⁺ = 268. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.67 (t,2H, CH₂CH₂CHOH, J = 8.4 Hz); 2.48 (t, 2H, CH₂CNCHC, J = 12.5 Hz); 2.56(d, 2H, CCH₂CHCOH, J = 12.1 Hz); 4.16 (t, 1H, CH₂CNCHC, J = 12.1 Hz);4.60 (t, 1H, CNCCHOH, J = 8.4 Hz); 5.38 (s, 1H, OH); 6.79 (s, 1H, NCHC);8.03 (s, 1H, NCHNH); 8.26 (s, 1H, NH); 10.01 (s, 1H, COOH) 77

[M + H]⁺ = 234. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.65 (t, 4H, CH₂CH₂CH₂ J = 7.5 Hz);3.03 (d, 2H, CCH₂CHCOOH, J = 10.5 Hz); 4.16 (t, 1H, NCHCH₂, J = 10.5Hz); 6.84 (d, 1H, SCCH, J = 3.4 Hz); 6.97 (dd, 1H, SCHCH, J = 5.0 Hz);7.39 (d, 1H, SCHCH, J = 5.0 Hz); 10.01 (bs, 1H, OH) 78

[M + H]⁺ = 248. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CCH₂CH₂CH₂, J = 7.5 Hz); 2.65 (t, 4H, CH₂CH₂CH₂ J = 7.5 Hz);3.03 (d, 2H, SCCH₂CHC, J = 10.5 Hz); 3.67 (s, 3H, CH₃); 4.16 (t, 1H,NCHCOCH₃, J = 10.5 Hz); 6.84 (d, 1H, SCCH, J = 3.4 Hz); 6.97 (dd, 1H,SCHCHCH, J = 5.0 Hz, J = 3.4 Hz); 7.39 (d, 1H, SCH, J = 5.0 Hz) 79

[M + H]⁺ = 192. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.20 (t, 2H, CCH₂CH₂N, J = 7.0 Hz); 3.93 (t, 2H, CCH₂CH₂N, J = 7.0 Hz);7.76 (s, 1H, CH) 80

[M + H]⁺ = 220. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.95 (t, 2H, NCH₂CH₂C, J = 6.6 Hz); 3.89 (t, 2H, NCH₂CH₂C, J = 6.6 Hz);8.32 (s, 2H, CH₂CCH); 8.97 (s, 1H, NCHN) 81

[M + H]⁺ = 220. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CCH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CCH₂CH₂CH₂,CCH₂CH₂CH₂, J = 7.5 Hz); 2.95 (t, 2H, CNCH₂CH₂C, J = 8.1 Hz); 3.89 (t,2H, CNCH₂CH₂C, J = 8.1 Hz); 7.38 (d, 1H, CCHCHN, J = 5.0 Hz); 9.20 (d,1H, CCHCHN, J = 5.0 Hz); 9.28 (s, 1H, CCHN) 82

[M + H]⁺ = 235. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.65 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.74 (d, 2H, CCH₂CHCOOH, J = 12.1 Hz); 4.16 (t, 1H, NCHCH₂C, J = 12.1Hz); 7.22 (s, 1H, SCHC); 8.98 (s, 1H, SCHN); 10.01 (bs, 1H, OH) 83

[M + H]⁺ = 263. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.65 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.74 (d, 2H, CCH₂CHCOOH, J = 12.1 Hz); 4.16 (t, 1H, NCHCOOH, J = 12.1Hz); 7.23 (dd, 1H, NCHCHCH, J = 4.7 Hz, J = 7.5 Hz); 7.29 (d, 1H, NCCH,J = 7.8 Hz); 7.66 (dd, 1H, NCHCHCH, J = 7.5 Hz, J = 7.8 Hz); 8.62 (d,1H, NCHCHCH, J = 4.7 Hz); 10.01 (bs, 1H, OH) 84

[M + H]⁺ = 234. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.65 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.09 (d, 2H, CCH₂CHCOH, J = 11.7 Hz); 4.16 (t, 1H, NCHCH₂C, J = 11.7Hz); 7.12 (d, 1H, SCHCH, J = 4.8 Hz); 7.40 (d, 1H, SCHCH, J = 4.8 Hz);7.46 (s, 1H, SCHC); 10.01 (bs, 1H, OH) 85

[M + H]⁺ = 252. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.65 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.99 (d, 2H, CCH₂CHCOOH, J = 10.5 Hz); 4.16 (t, 1H, CNCHCH₂, J = 10.5Hz); 6.37 (d, 2H, OCHCHCH, J = 3.0 Hz); 7.39 (s, 1H, OCH); 10.01 (bs,1H, OH) 86

LC/MS: an individual peak at a retention time of 1.01 min, [M]⁺ = 238.¹H-NMR (D₆-DMSO, 400 MHz) δ_(H), 1.79-1.86 (m, 2H, CH₂CH₂CH₂), 2.30 (s,3H, CH₃), 2.57 (t, J = 6.4 Hz, 4H, CH₂CH₂CH₂), 3.04 (t, J = 7.5 Hz, 2H,CH₂CH₂N), 3.94 (t, J = 7.5 Hz, 2H, CH₂CH₂N), 7.06 (s, 1H, CH(thiazole)).87

[M + H]⁺ = 222. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.46 (s, 3H, CH₃); 2.68 (t, 4H,CH₂CH₂CH₂, J = 7.5 Hz); 4.08 (t, 2H, CNCH₂CH₂N, J = 5.8 Hz); 4.50 (t,2H, CNCH₂CH₂N, J = 5.8 Hz); 7.26 (s, 1H, CHNCH₂CH₂N); 7.49 (s, 1H,CHNCCH₃) 88

[M + H]⁺ = 226. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.60 (dt,2H, CHCH₂CH₂NC, J = 9.2 Hz, J = 7.1 Hz); 1.84 (quint, 2H, CH₂CH₂CH₂, J =7.5 Hz); 2.10 (bs, 1H, NHCHCH₂CH₂N); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5Hz); 3.27 (t, 4H, NHCH₂CH₂NH, J = 7.5 Hz); 3.35 (d, 2H, NHCH₂CH, J = 9.9Hz); 3.56 (m, 1H, CH); 3.68 (t, 2H, CHCH₂CH₂N, J = 7.1 Hz); 4.07 (bs,1H, NHCH₂CH₂NH) 89

LC/MS: an individual peak at a retention time of 1.01 min, [M]⁺ = 227.¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.60 (m, 2H, morph), 1.80(quint, 2H, COCH₂CH₂CH₂CO, J = 6.6 Hz), 2.60 (t, 4H, COCH₂CH₂CH₂CO, J =6.6 Hz), 2.70 (m, 1H, morph), 2.90 (m, 1H, morph), 3.15 (m, 2H, CH₂CH),3.65 (m, 3H, morph + CH₂N), 3.80 (m, 1H, morph), 3.85 (d, 1H, morph, J =12.2 Hz), 9.45 (s, 3H, NH + HCl) 90

LC/MS: an individual peak at a retention time of 0.21 min, [M + H]⁺ =227. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.64 (m, 1H, morph),1.75 (m, 1H, morph), 1.84 (quint, 2H, COCH₂CH₂CH₂CO, J = 6.6 Hz), 2.61(t, 4H, COCH₂CH₂CH₂CO, J = 6.6 Hz), 3.02 (m, 1H, morph), 3.16 (m, 2H,CH₂CH), 3.47 (m, 1H, morph), 3.68 (m, 3H, morph + CH₂N), 3.86 (d, 1H,morph, J = 12.2 Hz), 3.99 (d, 1H, morph, J = 12.2 Hz), 9.45 (s, 3H, NH +HCl) 91

[M + H]⁺ = 220. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.20 (t, 2H, NCH₂CH₂C, J = 7.0 Hz); 3.93 (t, 2H, NCH₂CH₂C, J = 7.0 Hz);7.35 (d, 1H, NCCH, J = 8.0 Hz); 7.77 (dd, 1H, NCHCHCH, J = 5.1 Hz, J =8.0 Hz); 9.18 (d, 1H, NCHCHCH, J = 5.1 Hz) 92

[M + H]⁺ = 208.11 ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.20 (t, 2H, CCH₂CH₂N, J = 7.0 Hz); 3.93 (t, 2H, CCH₂CH₂N, J = 7.0 Hz);5.90 (s, 1H, NCCH); 7.30 (s, 1H, NNHCH); 12.06 (bs, 1H, NH) 93

[M + H]⁺ = 191. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.20 (t, 2H, CCH₂CH₂N, J = 7.0 Hz); 3.93 (t, 2H, CCH₂CH₂N, J = 7.0 Hz);6.91 (d, 1H, NCCH, J = 4.6 Hz); 7.72 (d, 1H, NSCH, J = 4.6 Hz) 94

[M + H]⁺ = 209. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.20 (t, 2H, CCH₂CH₂N, J = 7.0 Hz); 3.93 (t, 2H, CCH₂CH₂N, J = 7.0 Hz);6.80 (s, 1H, NCCH); 7.10 (s, 1H, NOCH) 95

[M + H]⁺ = 209. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.95 (t, 2H, CCH₂CH₂N, J = 7.7 Hz); 3.89 (t, 2H, CCH₂CH₂N, J = 7.7 Hz);8.38 (s, 1H, NCHC); 9.10 (s, 1H, NOCH) 96

[M + H]⁺ = 209. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.94 (t, 2H, CCH₂CH₂N, J = 7.2 Hz); 3.93 (t, 2H, CCH₂CH₂N, J = 7.2 Hz);6.29 (s, 1H, NOCCH); 8.39 (s, 1H, ONCH) 97

[M + H]⁺ = 220. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.20 (t, 2H, NCH₂CH₂C, J = 7.0 Hz); 3.93 (t, 2H, NCH₂CH₂C, J = 7.0 Hz);6.42 (d, 1H, CCHCHN, J = 5.1 Hz); 8.73 (d, 1H, CCHCHN, J = 5.1 Hz); 9.03(s, 1H, NCHN) 98

[M + H]⁺ = 220. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.94 (t, 2H, NCH₂CH₂C, J = 7.2 Hz); 3.93 (t, 2H, NCH₂CH₂C, J = 7.2 Hz);7.30 (d, 1H, CHCHCH, J = 5.2 Hz); 8.70 (d, 2H, CHCHCH, J = 5.2 Hz) 99

[M + H]⁺ = 207. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.20 (t, 2H, NCH₂CH₂C, J = 7.0 Hz); 3.93 (t, 2H, NCH₂CH₂C, J = 7.0 Hz);5.91 (d, 1H, CCHCHCH, J = 4.0 Hz); 6.07 (d, 1H, CCH, J = 4.0 Hz); 6.56(s, 1H, NHCH); 11.21 (bs, 1H, NH) 100

[M + H]⁺ = 239. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.94 (t, 2H, CCH₂CH₂N, J = 7.2 Hz); 3.93 (t, 2H, CCH₂CH₂N, J = 7.2 Hz);4.02 (s, 3H, CH₃); 7.02 (s, 1H, CH) 101

[M + H]⁺ = 204. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CCH₂CH₂CH₂C, J = 7.5 Hz); 2.00 (quint, 2H, CCH₂CH₂CH₂N, J =7.4 Hz, J = 6.0 Hz); 2.68 (t, 4H, CCH₂CH₂CH₂C, J = 7.5 Hz); 2.94 (t, 2H,CCH₂CH₂CH₂N, J = 7.4 Hz); 3.68 (t, 2H, CCH₂CH₂CH₂N, J = 6.0 Hz); 6.91(d, 1H, SCCH, J = 3.4 Hz); 6.96 (dd, 1H, CHCHCH, J = 5.0 Hz, J = 3.4Hz); 7.36 (d, 1H, SCH, J = 5.0 Hz) 102

[M + H]⁺ = 233. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CCH₂CH₂CH₂C, J = 7.5 Hz); 2.00 (tt, 2H, NCH₂CH₂CH₂C, J = 6.0Hz, J = 7.0 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz); 2.77 (t, 2H,NCH₂CH₂CH₂C, J = 7.0 Hz); 3.68 (t, 2H, NCH₂CH₂CH₂C, J = 6.0 Hz); 7.23(dd, 1H, CNCHCH, J = 4.7 Hz, J = 7.5 Hz); 7.29 (d, 1H, CCH, J = 7.8 Hz);7.66 (dd, 1H, CCHCHCH, J = 7.5 Hz, J = 7.8 Hz); 8.62 (d, 1H, NCHCHCH, J= 4.7 Hz) 103

[M + H]⁺ = 253. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.95 (t, 2H, NCH₂CH₂C, J = 8.1 Hz); 3.89 (t, 2H, NCH₂CH₂C, J = 8.1 Hz);7.39 (d, 1H, NCHCCH, J = 8.2 Hz); 7.57 (d, 1H, NCCH, J = 8.2 Hz); 8.32(s, 1H, CCHN) 104

[M + H]⁺ = 243. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.94 (t, 2H, CCH₂CH₂N, J = 7.2 Hz); 3.93 (t, 2H, CCH₂CH₂N, J = 7.2 Hz);7.02 (s, 1H, CH) 105

[M + H]⁺ = 253. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CCH₂CH₂CH₂C, J = 7.5 Hz); 2.00 (m, 2H, CCH₂CH₂CH₂N); 2.68(t, 4H, CH₂CH₂CH₂, J = 7.5 Hz); 2.94 (t, 2H, CCH₂CH₂CH₂N, J = 7.4 Hz);3.68 (t, 2H, CCH₂CH₂CH₂N, J = 6.0 Hz); 4.02 (s, 3H, CH₃); 7.02 (s, 1H,CH) 106

[M + H]⁺ = 257. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CCH₂CH₂CH₂C, J = 7.5 Hz); 2.00 (m, 2H, CCH₂CH₂CH₂N); 2.68(t, 4H, CCH₂CH₂CH₂C, J = 7.5 Hz); 2.94 (t, 2H, CCH₂CH₂CH₂N, J = 7.4 Hz);3.68 (t, 2H, CCH₂CH₂CH₂N, J = 6.0 Hz); 7.02 (s, 1H, CH) 107

[M + H]⁺ = 257. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.20 (t, 2H, CCH₂CH₂N, J = 7.0 Hz); 3.93 (t, 2H, CCH₂CH₂N, J = 7.0 Hz);6.40 (s, 1H, Indole-3); 7.26 (d, 1H, Indole-7, J = 7.9 Hz); 7.39 (m, 2H,Indole-4, Indole-6); 7.52 (dd, 1H, Indole-5, J = 7.4 Hz, J = 7.9 Hz);10.80 (s, 1H, NH) 108

[M + H]⁺ = 233. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CCH₂CH₂CH₂C, J = 7.5 Hz); 2.00 (tt, 2H, NCH₂CH₂CH₂C, J = 6.0Hz, J = 7.8 Hz); 2.38 (t, 2H, NCH₂CH₂CH₂C, J = 7.8 Hz); 2.68 (t, 4H,CCH₂CH₂CH₂C, J = 7.5 Hz); 3.68 (t, 2H, NCH₂CH₂CH₂C, J = 6.0 Hz); 7.49(d, 2H, CCHCHN, J = 5.5 Hz); 8.64 (d, 2H, CCHCHN, J = 5.5 Hz) 109

[M + H]⁺ = 249. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.95 (t, 2H, NCH₂CH₂C, J = 8.1 Hz); 3.89 (t, 2H, NCH₂CH₂C, J = 8.1 Hz);3.94 (s, 3H, CH₃); 6.82 (d, 1H, CCHCHCN, J = 9.2 Hz); 7.39 (d, 1H,CCHCHCN, J = 9.2 Hz); 8.32 (s, 1H, CCHN) 110

[M + H]⁺ = 191. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.20 (t, 2H, CCH₂CH₂N, J = 7.0 Hz); 3.93 (t, 2H, CCH₂CH₂N, J = 7.0 Hz);7.22 (s, 1H, SCHC); 8.98 (s, 1H, SCHN) 111

[M + H]⁺ = 209. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.94 (t, 2H, CCH₂CH₂N, J = 7.2 Hz); 3.93 (t, 2H, CCH₂CH₂N, J = 7.2 Hz);7.76 (s, 1H, NCHC); 8.84 (s, 1H, CHOC) 112

[M + H]⁺ = 208. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);2.95 (t, 2H, CCH₂CH₂N, J = 6.6 Hz); 3.89 (t, 2H, CCH₂CH₂N, J = 6.6 Hz);7.63 (s, 2H, NCHC); 12.61 (bs, 1H, NH) 113

[M + H]⁺ = 220. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.20 (t, 2H, NCH₂CH₂C, J = 7.0 Hz); 3.93 (t, 2H, NCH₂CH₂C, J = 7.0 Hz);7.91 (s, 1H, CNCHCHN); 8.71 (s, 1H, CNCHCHN); 8.75 (s, 1H, CCHN) 114

[M + H]⁺ = 258. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.68 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);3.20 (t, 2H, CCH₂CH₂N, J = 7.0 Hz); 3.93 (t, 2H, CCH₂CH₂N, J = 7.0 Hz);6.78 (dd, 1H, CCHNCHCH, J = 6.8 Hz, J = 7.0 Hz); 7.18 (dd, 1H,CCHNCHCHCH, J = 9.0 Hz, J = 6.8 Hz); 7.43 (d, 1H, CNCCH, J = 9.0 Hz);7.68 (s, 1H, CCHN); 8.43 (d, 1H, CCNCH, J = 7.0 Hz) 115

[M + H]⁺ = 194. ¹H-NMR (400.13 MHz, DMSO-d₆, δ, m.d., J/Hz): 1.84(quint, 2H, CH₂CH₂CH₂, J = 7.5 Hz); 2.65 (t, 4H, CH₂CH₂CH₂, J = 7.5 Hz);5.36 (s, 2H, CCH₂N); 6.87 (s, 1H, NCHC); 7.79 (s, 1H, NCHNH); 8.50 (s,1H, NH)

Example 10 Assessment of the Efficiency of Compounds in an AcuteRhinosinusitis Rat Model

Morphological studies of histologic preparations were conducted with aLeica DMLS light-optical microscope (Leica Microsystems, Germany).Micro-morphometric assessment was performed by using an ocularmicrometer on a Leica DMLB microscope.

Acute rhinosinusitis was induced by intranasal administration of 20 μlof 7.5% formalin solution (aqueous solution comprising 40% formaldehyde,8% methyl alcohol, and 52% water) to each nasal passage of rats.

Administration of formalin to rat nasal passages leads to thedissemination of inflammation to adjacent tissues, resulting in aclinical pattern similar to the symptoms of rhinosinusitis in a human.

After an acclimatization period, the following groups were formed:

-   -   intact animals administered intragastrically a saline solution        in an amount of 0.2 ml, the induction of acute rhinosinusitis        was not performed;    -   a control groupconsisted of the animals administered        intragastrically a saline solution in an amount of 0.2 ml for 7        days after induction of acute rhinosinusitis;    -   animals administered intramuscularly dexamethasone at a dose of        0.33 mg/kg for 7 days after induction of acute rhinosinusitis;        and    -   animals administered the tested compounds at a dose of 27 mg/kg        for 7 days after induction of acute rhinosinusitis.

Clinical observation of each animal was performed every day at leasttwice daily.

In the experiment with Wistar rats, the induction of acuterhinosinusitis by administration of a 7.5% formalin solution to nasalpassages caused in the control group of animals pronounced pathologicalchanges characterizing the development of an acute inflammation processin the nasal mucous. The caused pathology was characterized bycongestion, hyperplasia, focal necrosis of the nasal meatus mucousmembrane, an increased number of caliciform cells, pronouncedinfiltration by mononuclear cells and leucocytes, and mucushyperproduction by submucosal glands.

The mucous and submucous membranes of both nasal passages (respiratoryand olfactory regions) of the experimental animals were subjected to amorphological analysis to evaluate a specific activity of the compounds.

After completion of the clinical phase of the experiment, the materialderived from the animals (nose, nasolabial triangle) was dissected outand fixed in a 10% formalin solution for 24 hours and then decalcifiedin a 12% “De Castro” solution, after that the material was subjected toa standard treatment in alcohols with progressively increasingconcentrations (70-95%), xylene and paraffin to produce histologicpreparations with a thickness of serial paraffin sections of 3-5 μm. Formicroscopic examination, the sections were stained with hematoxylin andeosin. Detection of acid mukopolysaccharides, the production of which isincreased in an inflammation, was performed by histochemical staining ofthe preparation with Alcian Blue (pH 2.5). The comparison andhistological evaluation of changes were performed versus the group ofintact rats.

After slaughter, the gross appearance of inflammation in the nasalpassages was studied in each animal. Histological, hystochemical andmorphological studies of rats were intended to evaluate the followingcharacteristics of nasal passages: congestion of the mucous membrane;hyperplasia and necrosis of nasal epithelium, the number of caliciformcells within 1 mm of the mucous membrane of the nasal septum, and thecharacter of inflammation.

In this study, the efficiency of the mucociliary system was evaluated bythe number of caliciform cells and, as a consequence, microscopicchanges in the mucous membrane of the nasal passages.

Table 4.

The number of caliciform cells within 1 mm of the mucous membrane of thenasal septum

TABLE 4 The number of caliciform cells within 1 mm of the mucousmembrane of the nasal septum in rats, M ± m (data of severalexperiments) Group N The number of caliciform cells Intact 58 24.4 ±0.7  Control 58 43.3 ± 0.6  Dexamethasone 6 34.8 ± 2.1* Compound 1 1831.2 ± 1.2* Compound 3 12 35.8 ± 0.9* Compound 6 6 36.5 ± 0.8* Compound8 6 34.5 ± 0.8* Compound 124 12 37.6 ± 1.4* n is the number of animals,*p < 0.05 vs. control n is the number of animals

TABLE 5 Macroscopic characteristic of changes in the mucous membrane ofnasal passages in rats of different groups (data of several experiments)Muculent or mucopurulent Group n Without changes catarrh Intact 58 58 0Control 58 0 58 Dexamethasone 6 3 3 Compound 1 18 5 13 Compound 3 12 5 7Compound 6 6 2 4 Compound 7 18 5 13 Compound 8 6 3 3 Compound 124 12 4 8Compound 20 8 4 4 Compound 2 8 5 3 Compound 28 8 4 4 Compound 76 8 2 6Compound 56 8 5 3 Compound 65 8 4 4 Compound 75 8 3 5 Compound 70 8 4 4Compound 21 8 3 5 Compound 27 8 4 4 Compound 32 8 3 5 Compound 33 8 3 5Compound 44 8 4 4 n is the number of animals

As can be seen from tables 4 and 5, the compounds of general formula I(without any limitation to the studied compounds) effectively maintainthe efficiency of the mucociliary system and show therapeutic efficiencyin the rhinosinusitis model. The pharmacological action of the studiedcompounds was expressed in more pronounced regeneration of theepithelium, a reduction in the number of caliciform cells and mucushypersecretion.

Example 11 Antiviral Activity of Compounds of Formula (I) AgainstCoxsackie Virus In Vivo

The study used trypsin-dependent strain HCXV A2 previously adapted andcausing death of mice from Coxsackie virus infection.

The experiment was carried out by using white mice weighed 6 to 7 g. Theanimals were infected intramuscularly with a dose of 0.1 ml/mouse. Theinfectious dose used in the experiment was 10LD₅₀ causing lethality inmice.

The ability of the compounds to provide a therapeutic effect wasevaluated by the mortality rate in HCXV A2 virus-infected mice in thecontrol group, relative to the untreated group of mice.

The studied compounds and placebo were administered orally according tothe treatment scheme. The placebo administered to mice consisted of asaline solution. Intact animals served as a negative control were holdunder the same conditions as the experimental animals, in separaterooms.

The animals used in the experiment were divided into groups by 14-15animals. Compounds were administered at a dose of 30 mg/kg of bodyweight. The studied compounds were administered orally once daily for 7days (first administration was performed at 24 hours after theinfection). The animals were monitored for 15 days, during which theanimals were weighed every day and the mortality rate was registered.

During the study of the effectiveness of the tested compounds in HCXV A2virus infection, non-specific fatal cases were not registered in thecontrol group of intact animals.

Compounds of general formula (I) had a protective effect against theexperimental Coxsackie virus infection by decreasing the mortality rateamong the animals and increasing their average-expectancy life. Data ofsome particular compounds of formula (I) (without any limitation to therecited compounds) are represented in the table (Table 6).

The described antiviral activity of the tested compounds demonstratesthat these chemical compounds may be used as effective medicaments inHCXV enterovirus infection.

TABLE 6 Efficiency of the compounds of general formula (I) againstCoxsackie A2-virus infection in the mice model. Dose of tested com-Total pounds number Total Average and of mor- expectancy Pro- Testedreference animals tality life (days) tective com- preparation in a rate,Vs. index pounds mg/kg group % Relative control (%) Compound 30 15 40.024.9 +14.2 45 12 Compound 30 15 46.7 19.0 +8.3 36 13 Compound 30 15 50.021.4 +10.4 36 14 Compound 30 15 50.0 23.8 +13.1 36 23 Compound 30 1560.0 13.1 +2.4 18 30 Compound 30 15 53.3 16.6 +5.9 27 35 Compound 30 1553.3 16.7 +6.0 27 36 Compound 30 15 53.3 17.7 +7.0 27 89 Virus 15 73.310.7 control Compound 30 14 35.7 25.9 +15.1 50 90 Compound 30 14 35.727.0 +16.2 50 67 Virus 14 71.4 10.8 control Compound 30 14 35.7 27.3+14.3 50 75 Compound 30 14 35.7 26.7 +13.7 50 29 Compound 30 14 42.922.4 +9.5 40 2 Virus 14 71.4 13.0 control Compound 30 14 42.9 22.2 +10.033 32 Compound 30 14 28.6 32.3 +20.1 55 44 Compound 30 14 35.7 28.6+16.4 44 71 Virus 14 64.3 12.2 control

Example 12 Antiviral Action of the Compounds of General Formula (I)Against Mouse-adapted RS Virus

Antiviral efficiency of chemical compounds against RSV in experimentalmouse model in vivo was determined for human virus hRSV that waspreviously adapted to the growth in mouse lungs. The animals wereinfected with the virus at a dose of 5.0 log TCID₅₀ intranasally underbrief ether anesthesia in a volume of 0.05 ml/mouse. The testedcompounds were administered orally once daily for 5 days according tothe treatment scheme at a dose of 30 mg/kg. The first administration wasperformed at 24 hours after infection. The placebo administered to miceconsisted of a saline solution. Intact animals served as a negativecontrol were hold under the same conditions as the experimental animals,in separate rooms. Experimental groups comprised 12 animals. Ribavirinat dose of 40 mg/kg was used as a reference preparation.

The antiviral activity of the tested compounds was determined by theefficiency for the prevention of a weight loss and by the suppression ofthe reproduction of hRSV in the mouse lungs by measuring a viral titerin the experimental groups versus the control group on days 5 and 7after infection.

The results of measuring the weight of animals for some particularcompounds of formula (I) (without any limitation to the recitedcompounds) are represented in the table 7. The virus control group had astatistically significant weight loss in the mice, compared to theintact animals. The antiviral activity of the compounds of generalformula (I) was evident in a body weight gain of the mice, compared tothe control animals.

TABLE 7 Average body weight of the mice on days 5 and 7 after infectionBody weight of the mice on days 5 and 7 after infection with hRSV (M ±SD), n = 6 Preparation Day 5 Day 7 Compound 1 16.43 ± 0.14# 17.98 ±0.26# Compound 117 16.07 ± 0.12# 16.48 ± 0.28# Compound 3 16.65 ± 0.28#17.32 ± 0.25# Compound 120 16.12 ± 0.27# 17.22 ± 0.20# Compound 4 16.77± 0.20  17.08 ± 0.32# Compound 5 16.02 ± 0.16# 17.78 ± 0.26# Compound121 16.35 ± 0.20# 17.38 ± 0.29# Compound 122 16.93 ± 0.32  16.37 ± 0.21#Compound 123 15.87 ± 0.20# 17.55 ± 0.53  Compound 124 16.43 ± 0.26#16.37 ± 0.43# Compound 6 16.47 ± 0.26# 17.02 ± 0.29# Compound 7 17.17 ±0.26# 18.53 ± 0.55  Compound 8 15.18 ± 0.18  17.13 ± 0.27# Compound 915.75 ± 0.33  16.18 ± 0.29# Compound 10 16.18 ± 0.29# 16.53 ± 0.20#Ribavirin 16.20 ± 0.24# 17.23 ± 0.22# Virus control 15.45 ± 0.25  15.32± 0.31  Intact 17.30 ± 0.19# 18.00 ± 0.24# #statistically significantdifferences vs. the control animals (t-criterion, p < 0.05).

In addition, the therapeutic action of the compounds of general formula(I) was evaluated by their ability to suppress the reproduction of hRSVvirus in the mouse lungs on days 5 and 7 after infection. A viral titerwas determined by the titration of a 10% suspension of lungs in Hep-2cell culture. The result was recorded at 2 days after incubation at 37°C. by TCID. The results of the determination of the infectious activityof hRSV in the mouse lung suspensions in Hep-2 cell culture afteradministration of the tested compounds and the reference preparation aregiven in Table 8. The administration of the compounds of general formulaI to the animals led to a reduction in the hRSV infectious activity.

The study of antiviral activity of the compounds of general formula (I)in mouse hRSV infection model showed that the claimed compoundsprevented a weight loss and reduced the virus reproduction in the lungsof the animals.

TABLE 8 Suppression of the reproduction of hRSV virus in mouse lungs Day5 Day 7 Preparation lg Δlg lg Δlg Compound 1 2.88 ± 0.59 1.73 ± 0.591.46 ± 0.17 2.34 ± 0.17 Compound 117 3.00 ± 0.41 1.60 ± 0.41 1.46 ± 0.242.22 ± 0.34 Compound 3 3.04 ± 0.42 1.56 ± 0.42 1.46 ± 0.17 2.18 ± 0.28Compound 120 3.04 ± 0.47 1.56 ± 0.47 1.50 ± 0.25 2.05 ± 0.25 Compound 42.58 ± 0.51 2.02 ± 0.51 1.38 ± 0.24 2.58 ± 0.53 Compound 5 2.17 ± 0.372.43 ± 0.37 0.88 ± 0.31 2.93 ± 0.31 Compound 121 3.08 ± 0.47 1.52 ± 0.471.50 ± 0.14 2.09 ± 0.22 Compound 122 3.04 ± 0.44 1.56 ± 0.44 1.75 ± 0.411.88 ± 0.47 Compound 123 2.50 ± 0.43 2.10 ± 0.43 1.33 ± 0.19 2.62 ± 0.50Compound 124 2.46 ± 0.22 2.14 ± 0.22 0.83 ± 0.37 2.97 ± 0.37 Ribavirin 2.1 ± 0.12  2.4 ± 0.12 1.15 ± 0.12  2.4 ± 0.12 Virus control 4.60 ±0.30  3.8 ± 0.29 * statistically significant differences vs. the controlanimals (t-criterion, p < 0.05).

Example 13 Antiviral Action of the Compounds of General Formula (I)Against RS Virus in a Model of Mice with a Suppressed Immune System

Antiviral activity of the chemical compounds against human respiratorysyncytial virus (strain A2, ATCC VR-1540 with an infectious titer of5×10⁶ TCID₅₀/ml) was assessed in a viral pneumonia model in Balb/c mice.The virus was inoculated to animals intranasally in a volume of 50 μlunder brief ether anesthesia. To suppress an immune response to RSvirus, animals were abdominally administered cyclophosphan at a dose of100 mg/kg 5 days before infection. The tested compounds wereadministered according to the treatment scheme once daily at a dose of30 mg/kg for 5 days, starting at 24 hours after infection. The activityof the compounds was assessed by a reduction in edema of the lungsinfected with respiratory syncytial virus compared to the control, onday 5 after infection.

The results represented in Table 9 for some particular compounds ofgeneral formula (I) (without any limitation to the recited compounds)show that infection of the animals with the virus led to the formationof severe pulmonary edema (3.15-2.05 score from possible 4). The usedcompounds of general formula (I) had a normalizing action on thestructure of the lung tissue.

TABLE 9 The degree of edema in RS-viral pneumonia in Balb/c mice on day5 after infection under conditions of administration of the testedcompounds and the reference preparation (M ± SD, n = 5) Degree ofpulmonary Tested compounds and Dose, edema on day 5 after referencepreparation mg/kg infection, score Virus control — 3.15 ± 0.22  Compound3 30  1.6 ± 0.89* Compound 1 30 1.3 ± 0.27 Ribavirin 50 1.75 ± 0.59*Virus control — 2.70 ± 0.25  Compound 5 30 1.10 ± 0.19* Compound 6 300.90 ± 0.22* Compound 4 30 1.95 ± 0.31  Compound 9 30 1.00 ± 0.17*Ribavirin 50 1.00 ± 0.17* Virus control — 2.05 ± 0.23  Compound 120 301.05 ± 0.14* Compound 121 30 0.90 ± 0.21* Compound 123 30 1.30 ± 0.17*Ribavirin 50 1.24 ± 0.18* *marked values were different from the controlvalues according to t-criterion (p < 0.05).

Example 14 Antiviral Activity of the Compounds of Formula (I) AgainstRhinovirus

The study was performed by using author's hRV strain deposited in theState Collection of viruses (GKV) (reg. No. 2730). The animals wereinfected with the virus intranasally under brief ether anesthesia in avolume of 0.05 ml/mouse.

The virus was previously titrated in mice to determine the efficiency ofthe compounds against hRV in an in vivo experimental model, then themice were infected, and the preparation was administered orally. On days2, 3 and 4 after infection, an infectious titer was assessed bytitration of a lung suspension in Hela cell culture.

The studied compounds and placebo (saline solution) were orallyadministered to the mice once daily for 5 days, starting 12 hours afterinduction. The compounds were administered at a dose of 30 mg/kg of bodyweight. Ten intact animals that were kept under the same conditions asexperimental animals in a separate room served as a negative control.

The antiviral activity of the tested compounds was evaluated on days 2,3 and 4 after infection by the dynamics of weight changes of the bodyand lungs in mice and by a reduction of the virus infectious activitydetermined in Hela cell culture. The infectious titer of RV virus in thelungs of the experimental group, compared to the titer in the controlgroup, was determined by TCID. A criterion of the antiviral efficiencyof the preparations was a difference between titers in the control(without preparation) and experimental groups expressed in logarithmunits—Δ lg TCID₅₀. The difference was calculated according to theformula: (log A)−(log B).

Results of measuring the animal weight for some particular compounds offormula (I) (without any limitation to the recited compounds) arerepresented in the table 10.

TABLE 10 Body weight of the mice after infection with hRV Dose Day afterinfection Preparation (mg/kg) 0 1 2 3 4 Compound 4 30 7.77 ± 7.27 ±12.66 ± 13.14 ± 13.23 ± 1.02 1.27# 2.32# 1.5*# 1.38* Compound 1 30 7.36± 8.2 ± 13.03 ± 13.47 ± 13.99 ± 0.97 4.25# 3.51# 1.36* 1.53* Ribavirin40 7.66 ± 8.81 ± 13.87 ± 13.11 ± 13.37 ± 0.89 5.94# 5.11* 1.37# 1.22*Intact 7.52 ± 8.41 ± 13.63 ± 14.33 ± 14.48 ± 0.05 0.84* 1.22* 1.23* 0.9*Virus 7.72 ± 7.54 ± 12.57 ± 12.63 ± 12.39 ± control 0.98 0.89# 1.58#1.13# 0.72# #statistically significant differences vs the intact animals(t-criterion, p < 0.05); *statistically significant differences vs. thecontrol animals (t-criterion, p < 0.05).

The development of the infectious process was associated with areduction in the body weight of the animals in the virus control group,wherein the body weight of the mice treated with the tested compounds ofgeneral formula (I) was statistically significantly different from thebody weight of the control animals on days 3 and 4.

The study of the lung weight of the mice in rhinovirus infection and thetherapeutic scheme of administration of the preparations showed thatduring the experiment, the lung weight of the infected mice exceeded thelung weight of the intact mice, indicating an active infectious process.On day 4, the lung weight of the mice being under the effect of thestudied preparations was significantly different from the virus controlgroup and was almost the same as the lung weight of the intact animals.Data of some particular compounds (without any limitation to the recitedcompounds) are represented in Table 11.

TABLE 11 Lung weight of the mice after infection with hRV Dose Day afterinfection Preparation (mg/kg) 2 3 4 Compound 4 30   142 ± 4.81*#  135.9± 4.18*#  134.2 ± 3.68*# Compound 1 30  136.9 ± 5.93*#  140.8 ± 5.14*#128.2 ± 5.81* Ribavirin 40 152.6 ± 4.55# 130.1 ± 5.4*# 120.5 ± 3.37*Intact 120.2 ± 2.39* 123.7 ± 2.75* 125.3 ± 3.65* Virus 153.8 ± 3.55#167.8 ± 4.16# 183.5 ± 3.03# control #statistically significantdifferences vs. the intact animals (t-criterion, p < 0.05);*statistically significant differences vs. the control animals(t-criterion, p < 0.05).

Results of the determination of hRV infectious activity in suspensionsof the mouse lungs in Hela cell culture after administration of someparticular compounds of general formula (I) (without any limitation tothe recited compounds) are represented in Table 12.

TABLE 12 Suppression of the reproduction of hRV virus in mouse lungsSuppression of the Infectious reproduction Infectious SuppressionInfectious Suppression titer of of the titer of the titer of of the thevirus virus in oft the virus reproduction the virus reproduction inlungs, mouse lungs, in lungs, of the virus in lungs, of the virus lgTCID₅₀ Δ lg lg TCID₅₀ in mouse lg TCID₅₀ in mouse Dose of Day 2 afterDay 3 after Day 4 after preparation, infection infection infectionPreparation mg/kg lg Δ lg lg Δ lg lg Δ lg Compound 1 30  2.9 ±  1.1 ±0.8 ± 1.7 ± 0.03 ± 2.18 ±  0.49 0.49 0.31 0.31 0.08 0.08 Compound 4 302.35 ± 1.65 ± 0.6 ± 1.9 ± 0 ± 0 2.2 ± 0.65 0.65 0.27 0.27 4.68 Ribavirin40 3.13 ± 0.88 ± 0.33 ±  2.18 ±   0.2 ±  2 ± 0.5 0.5 0.26 0.26 0.16 0.16Control 4.03 ± 2.5 ± 2.18 ± 0.38 0.2 0.31

The treatment with the compounds of general formula (I) resulted to areduction in hRV infectious activity on days 3 and 4 after infection.

The study of the antiviral activity of the compounds of general formula(I) in mouse hRV infection model showed that the claimed compoundsprevented a weight loss and an increase in the lung weight to the valuesobserved in the group of intact animals and reduces the virusreproduction in the animal lungs.

Example 15 Antiviral Activity of the Compounds of Formula (I) AgainstInfluenza Virus

The study was conducted by using influenza virus strainA/California/07/09 (H1N1) pdm09. White outbred female mice used in theexperiment weighing 14-16 g were divided to groups by 20 animals.

During the experiment, each animal was observed every day. Theobservation included the assessment of the general behavior and bodycondition of the animals. In days of administration of preparations, theobservation was conducted before administration of a preparation in acertain time and at about two hours after administration. The animalswere handled according to the International Standards.

The mice were infected with influenza virus A/California/07/09 (H1N1)pdm09 intranasally in a volume of 0.05 ml comprising 5 LD50.

The therapeutic effect of the compounds of general formula (I) wasstudied by oral administration of the compounds to the infected miceonce daily at a dose of 30 mg/kg/mouse at 24, 48, 72, 96, and 120 hoursafter infection with the virus. Mice of the control group wereadministered placebo under the same conditions (0.2 ml of a salinesolution). The animals were monitored for 14 days after infection andfatal cases caused by influenza pneumonia in the treated and controlgroups were registered. The specificity of animal death from influenzapneumonia was supported by the registration of anatomo-pathologicalchanges in the lungs of dead animals.

The activity of the compounds was evaluated by comparison of themortality rates between the groups of animals administered a preparationand placebo.

The expectancy life of the infected animals administered placebo was7.2±2.2 days at a mortality rate of 95%.

The mortality rate of the groups of animals administered the compoundsof general formula (I) was reduced by 30-60% and the expectancy life washigher than in the control mice. Data for some particular compounds ofgeneral formula (I) (without any limitation to the recited compounds)are represented in table 13.

TABLE 13 Mortality rate in experimental groups of animals Dose MortalityNo Preparation (mg/ml) rate, % 1 Compound 1 (KhS-8) 30 35.0 2 Compound 5(KhS-221-GI) 30 45.0 3 Compound 4 (KhS-217) 30 65.0 4 Compound 12 3060.0 5 Compound 20 30 50.0 6 Compound 23 30 40.0 7 Compound 24 30 55.0 8Compound 30 30 50.0 9 Compound 35 30 55.0 10 Compound 36 30 60.0 11Compound 83 30 45.0 12 Virus control 95.0 13 Intact 0.0

Example 16 Dosage Forms of the Compounds According to the Invention

The compounds according to the invention may be administered orally,intramuscularly or intravenously in a unit dosage form comprisingnon-toxic pharmaceutically acceptable carriers.

The compounds may be administered to a patient in daily doses of from0.1 to 10 mg/kg of body weight, preferably in doses of from 0.5 to 5mg/kg, one or more times a day.

In addition it should be noted that a particular dose for a particularpatient depends on many factors, including the activity of a certaincompound, patient's age, body weight, gender, general health conditionand diet, the time and route of administration of a pharmaceutical agentand the rate of its excretion from the body, a specific combination ofdrugs and the severity of a disease in an individual to be treated.

The pharmaceutical compositions according to the present inventioncomprise a compound of general formula (I) in an amount effective toachieve a desired technical result, and can be administered in a unitedosage form (for example, in a solid, semi-solid, or liquid form)comprising the compounds according to the present invention as an activeagent in a mixture with a carrier or an excipient suitable forintramuscular, intravenous, oral and sublingual administration,administration by inhalation, intranasal and intrarectal administration.The active ingredient can be in a composition together with conventionalnontoxic pharmaceutically acceptable carriers suitable for themanufacture of solutions, tablets, pills, capsules, coated pills,emulsions, suspensions, ointments, gels, and any other dosage forms.

As an excipient, various compounds can be used, such as saccharides, forexample, glucose, lactose, of sucrose; mannitol or sorbitol; cellulosederivatives; and/or calcium phosphates, for example, tricalciumphosphate or calcium hydrophosphate. As a binder, the followingcompounds can be used, such as a starch paste (for example, corn, wheat,rice, or potato starch), gelatin, tragacanth, methylcellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone. Optionally used disintegrants are theabove-mentioned starches and carboxymethylstarch, crosslinkedpolyvinylpyrrolidone, agar-agar, or alginic acid or a salt thereof, suchas sodium alginate.

Additives that can be optionally used are flowability-control agents andlubricants, such as silicon dioxide, talc, stearic acid and saltsthereof, such as magnesium stearate or calcium stearate, and/orpropylene glycol.

In preparing a unit dosage form, the amount of an active agent used incombination with a carrier can vary depending on a recipient to betreated and on a particular route of administration of a therapeuticagent.

For example, when the compounds according to the present invention areused in the form of a solution for injection, the amount of the activeagent in this solution is 0.01-5 wt. %. A diluent may be selected from a0.9% sodium chloride solution, distilled water, a Novocain solution forinjection, Ringer's solution, a glucose solution, and specificsolubilizing adjuvants. When the compounds according to the presentinvention are administered in tablet form, their amount is from 5.0 to500 mg per unit dosage form.

Dosage forms according to the present invention are prepared byconventional procedures, such as blending, granulation, forming coatingpills, dissolution, and lyophilization.

Tableted Form

A tableted form is prepared by using the following ingredients:

Active agent: Compound according to 2.00 mg  10 mg  100 mg the inventionor a pharmaceutically acceptable salt thereof Additives:Microcrystalline cellulose, 47.70 mg  70.55 mg  95.90 mg  MCC 102 (USP,Ph. Eur.); Lactose monohydrate 49.00 mg  67.50 mg  99.00 mg  (USP, Ph.Eur.); Sodium starch glycolate 0.50 mg 0.75 mg 1.50 mg (USP, Ph. Eur.);Talc 0.40 mg 0.60 mg 1.20 mg (USP, Ph. Eur.); Magnesium stearate (USP,0.40 mg 0.60 mg 2.40 mg Ph. Eur.) Weight of the tablet core 100.00 mg 150.00 mg  300.00 mg  Coating (USP, Ph. Eur.) 3.00 mg 4.50 mg 9.00 mgTablet weight 103.00 mg  154.50 mg  309.00 mg 

The components are mixed and compressed to form tablets.

Suppositories

Example of the Suppository Composition

Compound according to the invention or a 1-100 mg pharmaceuticallyacceptable salt thereof Cacao oil amount required to prepare asuppository

If necessary, rectal, vaginal, and urethral suppositories are preparedby using corresponding excipients.

Solution for Injection

Example of the composition of a solution for injections:

Compound according to the invention or a 1-50 mg pharmaceuticallyacceptable salt thereof Water for injection   2 ml

The invention claimed is:
 1. A compound of general formula I:

wherein m is an integer from 1 to 2; R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁,R^(e) ₁, and R^(f) ₁, each independently represents hydrogen,C₁-C₆alkyl; —NH₂, —NHC₁-C₆alkyl, hydroxyl, or C₁-C₆alkoxy; R₂ ishydrogen, C₁-C₆alkyl, —C(O)OH, —C(O)OC₁-C₆alkyl; R₃ is: 1) a 5-memberedsaturated or unsaturated heterocyclic group comprising from 1 to 4heteroatoms selected from N, O and S, optionally substituted with 1 to 3substituents selected from halogen, C₁-C₆alkyl, C₁-C₆alkoxy, —C(O)OH,—C(O)OC₁-C₆alkyl, —NHC(O)C₁-C₆alkyl, phenyl, or pyridinyl; 2) a6-membered saturated or unsaturated heterocyclic group comprising from 1to 2 heteroatoms selected from N and O, optionally substituted with agroup selected from halogen and C₁-C₆alkyl; 3) a 5-membered unsaturatedheterocyclic group comprising from 1 to 3 heteroatoms selected from Nand S, optionally substituted with 1 or 2 substituents selected fromC₁-C₆alkyl, condensed with a 6-membered unsaturated nitrogen-containingcyclic or heterocyclic group optionally substituted with 1 or 2substituents selected from hydroxyl, halogen or C₁-C₆alkyl; 4) a6-membered unsaturated cyclic or heterocyclic group comprising from 1 to2 nitrogen atoms, condensed with a 5- or 6-membered unsaturatedheterocyclic group comprising from 1 to 3 heteroatoms selected from Nand S; or 5) a group of the formula:

or a pharmaceutically acceptable salt thereof, with a proviso that thecompound is not a compound, wherein: when m is 1, R^(a) ₁, R^(b) ₁,R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁ are hydrogen and R₂ is —C(O)OCH₃,R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 1, R^(a) ₁ is an amino group and R^(b) ₁, R^(c) ₁, R^(d) ₁,R^(e) ₁, and R^(f) ₁ are hydrogen, or R^(e) ₁ is an amino group andR^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, and R^(f) ₁ are hydrogen and R₂ ishydrogen, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is —C(O)OH, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is —C(O)OH, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 2, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 2, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

when m is 1, R^(a) ₁, R^(b) ₁, R^(c) ₁, R^(d) ₁, R^(e) ₁, and R^(f) ₁are hydrogen and R₂ is hydrogen, R₃ is not:

and with a proviso that the compound is not the following compound:


2. The compound of claim 1, wherein R^(a) ₁ and R^(b) ₁ are hydrogen,methyl, amino, or hydroxyl; R^(c) ₁ and R^(d) ₁ are hydrogen, methyl,amino, or hydroxyl; R^(e) ₁ and R^(f) ₁ are hydrogen or methyl; R2 ishydrogen, methyl, carboxyl, methoxycarbonyl, or ethoxycarbonyl; R3 is agroup selected from:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1, which is:


4. A medicament for the treatment of a respiratory tract disease, whichis a compound as claimed in claim 1 or a pharmaceutically acceptablesalt thereof.
 5. The medicament of claim 4, wherein the respiratorytract disease is rhinosinusitis.
 6. The medicament of claim 4, whereinthe respiratory tract disease is caused by an RNA-comprising virus. 7.The medicament of claim 6, wherein the virus is selected from the groupconsisting of rhinovirus, Coxsackie virus, respiratory syncytial virus,and influenza virus.
 8. The medicament of claim 4, wherein the diseaseis exacerbations of asthma, chronic obstructive pulmonary disease,bronchitis and mucoviscidosis, which are caused by rhinovirus, influenzavirus and/or respiratory syncytial virus.
 9. A pharmaceuticalcomposition for the treatment of a respiratory tract disease, comprisingan effective amount of a compound as claimed in claim 1 or apharmaceutically acceptable salt thereof, and a phaurmaceuticallyacceptable carrier.
 10. The pharmaceutical composition of claim 9,wherein the respiratory tract disease is rhinosinusitis.
 11. Thepharmaceutical composition of claim 9, wherein the respiratory tractdisease is caused by an RNA-comprising virus.
 12. The pharmaceuticalcomposition of claim 11, wherein the virus is selected from the groupconsisting of rhinovirus, Coxsackie virus, respiratory syncytial virus,and influenza.
 13. The pharmaceutical composition of claim 9, whereinthe disease is exacerbations of asthma, chronic obstructive pulmonarydisease, bronchitis and mucoviscidosis, which are caused by rhinovirus,influenza virus and/or respiratory syncytial virus.